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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     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|   | *This staff working paper was discussed at the Council's             March 2003 meeting.             It was prepared by staff solely to aid discussion, and does not represent             the official views of the Council or of the United States Government.*
Staff Working Paper
**Stronger, Long-Lasting Skeletal               Muscles through Biotech? 1**

**Introduction**              Our muscles are essential to human life in a variety of ways. They               are central components of physical strength and speed, attributes               that are admired and celebrated in most human cultures. Our mobility               depends on muscles, whether we use them to walk, or when we just               use them to turn the wheel of a car or put our foot down on the               accelerator or the brake. As a basic component of physical vigor               they also play a role in human attractiveness. As such, muscle tone               is a major contributor to the “sense of self” developed               by each person. Although there are several different types of muscles               in the human body, we will concentrate here on processes affecting               skeletal muscles.

The strength and fitness of healthy muscles are largely a function               of their exercise. In our youth, active use of our muscles in play               and in sports strengthens and develops them. At puberty, production               of estrogen and testosterone enhances these processes, so that the               peak of human muscular development is usually between 20 and 30               years of age. Except for people whose daily work requires much physical               exertion, maintaining peak muscular strength and endurance later               in life requires regular exercise and fitness training. Some pursue               this avidly, while others do not.

The strength and size of human muscles declines by about one-third               between the ages of 30 and 80.2 Diminished capacity or loss of a               previous ability to do a physical task is a common experience during               human aging. The age-related loss of muscle size and strength has               been named “sarcopenia”.3 In addition, there are a variety               of diseases of muscle tissue (muscular dystrophies), many caused               by specific genetic mutations.

We have an increased understanding of how many of the important               genes in muscle cells function and are regulated.4 The parallel               development of gene therapy techniques for efficient and controlled               expression of genes is beginning to open up new possibilities for               treating muscular dystrophies as well as maintaining “youthful”               muscle size and strength               during the aging process. It is thus timely to begin discussions               of the ends to which such increased understanding and power to modify               should be put when it comes to human muscles.

As discussed in more detail below, biotechnological approaches               to repair and strengthening of diseased and aging skeletal muscles               have been demonstrated in experimental animals. The application               of these approaches (once they are shown to be safe and effective)               to treat human muscular dystrophies clearly falls within current               understandings of appropriate therapy. A more difficult judgment               is whether we should               extend the application of these approaches to a variety of other               situations that are currently “beyond therapy”.

Muscles do not generate human strength and speed in isolation.               Muscles need to be physically integrated with, and function harmoniously               through their attachments to nerves, tendons, ligaments, and bones.               While the focus in this paper is on the activity of muscle cells,               we should remain alert to the possibility that biotechnological               approaches that strengthen only muscles may lead to imbalances in               the interactions with other components of the body, and subsequent               malfunction.

**Muscles in idealizations of male human form**

Muscles play a prominent role in idealizations of male human form.               A classical picture of excellence of the youthful male human form               is Michelangelo’s sculpture of David, completed around 1504               (see Figure 1). Here the muscles are depicted as well- 

 Figure 1. Michelangelo's David                    (ca. 1504)ihttp://www.sculpturegallery.com/sculpture/david.html

Figure 2. Arnold Schwarzenegger (ca. 1980)iihttp://www.schwarzenegger.com/en/athlete/index.asp?sec=athlete

proportioned but without much articulation of individual muscles.               The strength and              power of David’s skeletal muscles shine through the marble,               and leave us with a mental picture of the classical ideal of muscular               development and proportion.

A more contemporary idealization of the male human form is the               picture of the modern male body-building champion and actor, Arnold               Schwarzenegger (Figure 2). Through specialized weight training and               alleged use of anabolic steroids, his muscles (particularly the               biceps) have become much larger than those pictured in the statue               of David, and the different groups of skeletal muscles are individually               articulated.

Although different in proportion and muscle articulation, both               the classical and contemporary pictures testify to the importance               of muscles in images of male strength and power. Large muscles were               also supposed to help males attract females, a point that is still               emphasized by males working out in gyms. “I am exercising               and increasing the size of my muscles so that the chicks will notice               me”.

Interestingly, female body-builders reportedly initially pursued               the same path illustrated by the picture of Arnold Schwarzenegger.               The result was female body-building champions with smaller but similarly               individually developed and articulated skeletal muscles. More recently               there has been an “aesthetic” reaction against the resulting               female muscle “overdevelopment” and, commercially at               least, the more popular and profitable activity today is women’s               fitness competitions.

Genetic treatments are not the only biotechnological approach to               increasing muscle size and strength. Anabolic steroids are among               the most widely used chemical compounds that are used in combination               with weight lifting to increase muscle size and strength. Examples               of such compounds include methandrostenolone (Dianabo 1), Boldenone               (Equip-gan), Stanazolol (Winstrol V) and Drostanolone (Masteron).               As information about their effects has diffused throughout American               society, they are coming to be used more and more by professional               and amateur athletes. Use of some of them is banned by anti-doping               organizations. Many (including the ones listed above), are listed               as available for sale on the Internet.

*Cellular multiplication and differentiation in skeletal muscle*

The major cell type present in skeletal muscle fibers is the multinucleated               myotube. These fibers arise from the fusion of mononucleated myoblast               cells with each other and with pre-existing myotubes. Myoblasts,               in turn, are formed by differentiation of a particular stem cell               found in muscle tissue, called a satellite cell.5

The multiplication and differentiation of satellite cells into               myoblasts is regulated by several specific protein growth factors               (primarily insulin-like growth factor 1 (IGF-1) and hepatocyte growth               factor (HGF)) and also influenced by hormones such as growth hormone,               testosterone and estrogen. Secretion of growth hormone by the pituitary               acts on the liver to stimulate synthesis and release of IGF-1, which               is released into the circulation (Figure 3). In muscle tissue, IGF-1               binds to specific receptors on the surface of satellite cells to               stimulate cell multiplication, producing more satellite cells, and               differentiation of satellite cells into myoblasts (see Figure 4).             

PITUITARY***Growth Hormone (GH)****Secreted*              LIVER***IGF-1****released*              SKELETAL MUSCLE growth stimulated

Figure 3. Hormone action and muscle growth stimulation

Importantly, a slightly different form of IGF-1 (mIGF-1) is also               produced locally in muscle tissue in response to stretching the               muscles (exercise). This form is thought to act the same way as               circulating IGF-1 does in stimulating satellite cell multiplication               and differentiation. However, because mIGF-1 is slightly different               in chemical structure from IGF-1 produced in the liver, mIGF-1 apparently               does not enter the circulation, so its effects can be restricted               to promoting growth and repair of muscle tissue locally.

It is a common human experience that muscle size and strength can               be increased by exercise. The number of muscle fibers increases               as a consequence of exercise-induced stimulation of the multiplication               and differentiation of muscle stem cells. Exercise both transiently               damages muscles and causes them to increase in size and strength.             

While exercise was previously the only way to do this, biotechnological               research and 

 Figure 4. Schematic diagram of*some* important processes               in skeletal muscle fiber growth and repair.

development have introduced new possibilities. The genes for animal               and human IGF-1 have been cloned and their DNA sequences determined.               Gene expression vectors have been developed that permit the regulated               production of IGF-1 proteins (both the liver and muscle forms) for               investigation. So IGF-1 genes can be introduced into cells and experimental               animals to determine the effect of enhanced IGF-1 (and/or mIGF-1)               production on muscle size and strength.

*Loss of muscle size and strength on aging: sarcopenia*

With aging, we become more sedentary and use our muscles less.               With aging the production of growth hormone and circulating IGF-1               also decreases. There is thus less IGF-1 available to keep the muscles               large, and they become smaller and weaker. In addition, aged muscle               cells are apparently less responsive to the action of IGF-1 and               mIGF-1 6 so that the impact of even vigorous exercise on muscle size               and strength diminishes with age. Figure 5 graphically illustrates               the appearance of leg muscles as they become smaller and weaker               with age (sarcopenia).              As we age, several things change that predispose to the development               of sarcopenia. We either reduce the output of, and/or become more               resistant to, anabolic stimuli to muscle such as central nervous               system input, growth hormone, estrogen, testosterone, dietary protein,               physical activity and insulin action. The loss of alpha-motor neuron               input to muscle that occurs with age7 is believed to be a critical               factor8. Nerve cell-muscle cell connections are critical to maintaining               muscle mass and strength. 

A loss of muscle size and strength in a significant problem for               older persons. While not painful or directly debilitating, sarcopenia is associated               with an increased tendency to fall and break bones. Such falls and               broken bones are major causes of morbidity among the elderly.
This image is from the informative                     Internet site www.sarcopenia.com.
Figure 5 – Illustrating progressive age-related loss of muscle               tissue (sarcopenia) iii

 

**Selective stimulation of skeletal muscle growth in experimental               animals.**

*Local injection of regulated exogenous “muscle-specific”               IGF-1 Gene*              Recombinant viruses, engineered to express a specific foreign gene,               are frequently used to stimulate the production of functionally               effective amounts of the foreign protein to treat disease. Recombinant               viruses created from genetically engineered human               Adenovirus-associated Virus (AAV) have proved to be efficient delivery               systems of foreign genes into muscle cells. As AAV is a small virus,               only small foreign genes can be used effectively with this virus.               Fortunately, the DNA sequence encoding IGF-1 is small enough to               function well in AAV-based recombinant viruses.

In experiments described by Barton-Davis and coworkers 9, AAV recombinant               viruses containing a rat IGF-1 gene were injected into the anterior               compartment of the rear legs of mice containing the extensor digitorum               longus (EDL) muscle. The resulting increased IGF-1 production promoted               an average increase of about 15% in EDL muscle mass and strength               in young adult mice. Strikingly, such injections led to a 27% increase               in the strength of the EDL muscles of 24-month (old) mice, thus               substantially reducing the decrease in EDL muscle size and strength               observed in untreated old mice.

In this study, approximately 1 x 1010 recombinant AAV particles               in 100 µliters of fluid were injected into a single small               muscle compartment of mice. If such treatments were eventually to               be applied to humans, large amounts of recombinant AAV containing               the human IGF-1 DNA sequence would be required. Assuming such future               treatments were shown to be safe and effective, producing sufficient               recombinant AAV to treat millions of dystrophic and aging humans               would remain a substantial logistical challenge. However, there               may be ways around this logistical problem involving the production               and transplantation of human muscle stem cells engineered to produce               more IGF-1 (see below).

*IGF-1 transgenic mice*

The ability to create transgenic mice, in which an appropriately               regulated foreign gene is expressed throughout embryonic and adult               life, offers another way to assess the biological role(s) of the               transgene product. Musaro et al10 introduced a rat mIGF-1 transgene               into early stage mouse embryos, where it became integrated with               mouse chromosomal DNA. The resulting transgenic mice produce substantial               amounts of rat mIGF-1, in addition their production of mouse IGF-1               and mIGF-1.

In these transgenic mice, the rat mIGF-1 transgene was connected               to gene expression regulatory elements that restricted production               of the rat mIGF-1 protein to muscle tissues containing primarily               fast twitch fibers. Embryonic development of these transgenic mice               proceeded normally. However, as early as 10 days after birth, enlargement               of skeletal muscles where rat mIGF-1 protein was being produced               was observed in the transgenic animals compared to the non-transgenic               control mice. 

Moreover, the skeletal muscle enlargement persisted as the transgenic               mice aged.              Muscle size and strength were maximal around six months in unmodified               (wild type) mice and decreased as expected by 20 months of age.               In contrast, at 20 months the size and strength of skeletal muscle               in the rat mIGF-1 transgenic mice remained at essentially the same               as at six months.

In previous studies of this type, the IGF-1 transgene was not connected               to gene expression regulatory elements that restricted production               of mIGF-1 to muscle tissue.               This led to overproduction of IGF-1 in the circulation, and eventually               to pathological enlargement of the heart muscle. The growing understanding               of muscle physiology at the molecular level coupled with sophisticated               genetic engineering has made it possible to enlarge skeletal muscles               selectively, without damaging heart muscles in the process.

These and other experimental results stimulate thought about possible               extensions of these approaches to humans. Similar procedures might               be useful treatments for various diseases of muscle tissue, and               well as a possible use in older persons to counteract sarcopenia.               However, each of the procedures described above has technical/logistic               problems that would need to be overcome before any treatment could               be applied on a large scale.

***Could* these biotechnological approaches be applied               to human muscles?**

Could the mIGF-1 gene procedures that increase skeletal muscle               size and strength in young and old experimental animals be adapted               for use in humans? Based on our current understanding, at least               three different approaches could be considered. First, one might               develop recombinant AAV-based virus vectors containing the human               mIGF-1 gene under the control of appropriate regulatory elements               that would limit its expression to muscle cells near the site of               injection. Alternatively, one might introduce an appropriately regulated               mIGF-1 gene into human embryos, as was done in the experiments with               mice. Finally, a combined approach might be developed in which one               first isolated human muscle stem (satellite) cells and expanded               them in vitro, next introduced an appropriately regulated human               mIGF-1 gene into those cells in vitro, and finally transplanted               the genetically modified satellite cells back into the muscles of               the person being treated.

The first approach would be similar to other human gene therapy               projects. The appropriately regulated human mIGF-1 gene would be               combined with a vector capable of efficient delivery to muscle cells,               perhaps AAV. This material could be produced in large volumes, carefully               characterized by tests in experimental animals, stored frozen and               used as needed. While the logistics of producing the large amounts               of recombinant AAV that would be required for treatment of thousands               or millions of patients are daunting, in principle this would be               possible. The advantages of this approach are 1) that it would develop               and use a single, well-characterized biological agent; 2) that treatment               could be started very slowly by introducing the recombinant mIGF-1               gene-containing AAV into one muscle at a time and evaluating its               effects; 3) that treatment could be stopped immediately if untoward               side effects developed. Disadvantages include 1) the possibility               that a large number of injections would be necessary to treat each               of the large number of human skeletal muscles; 2) the possibility               that this would not be an effective treatment for humans who had               antibodies to AAV as a consequence of a previous infection.

The second approach is a radical proposal, as it envisions treatment               of blastocyst stage human embryos in vitro with a genetic procedure               that was intended to change the early development of skeletal muscle               size and strength and reduce the rate of loss later in life. This               approach shares some advantages with the first approach in that               a single biological agent could be prepared and characterized that               could treat all embryos; 2) that only a single treatment early in               embryonic development would be needed, instead of multiple injections               into different muscles. The major disadvantages of this approach               are the difficult ethical questions it would raise.

The third approach depends upon the ability to isolate human muscle               stem (satellite) cells and expand them in vitro. The isolated human               muscle stem cells would then have their mIGF-1 production genetically               modified by introducing an appropriately regulated exogenous mIGF-1               gene copy. In theory, this could produce modified muscle stem cells               that multiplied continuously in vitro to produce larger numbers               of cells, and that differentiated appropriately in vitro. In this               case, genetically modified satellite cells would be injected into               the aging skeletal muscles. The advantages of this approach include               1) that it would develop and use a single, well-characterized biological               agent to modify the muscle stem cells in vitro and 2) the dose of               modified stem cells could be varied as necessary to optimize treatment               of individual skeletal muscles. The disadvantages include the possibility               that a separate preparation of muscle stem cells from each patient               to be treated would have to be made in order to get around the immune               rejection problem. 

Each of these approaches has advantages and disadvantages. Developing               any one of them would take a lot of time and money. Before genetic               treatments to increase muscle size and strength are tried in humans,               the US Food and Drug Administration would require demonstrations               that the proposed treatment is safe and effective. This will ensure               regulatory oversight of any initial experiments along these lines               with humans.

The initial steps in applying to normal humans the kinds of genetic               approaches to increasing muscle size and strength described here               will likely be performed in the course of using these procedures               to treat human muscle diseases. Clinical trials of regulated mIGF-1               gene delivery as a treatment for specific forms of muscular dystrophy               may begin within the next several years (Sweeney, personal communication).               Data on route of administration, optimal dose and possible side               effects will be obtained from these clinical trials. If efficacy               is demonstrated and side effects are small, one can imagine that               many people, young as well as old, might well be interested in receiving               genetic muscle treatments to enhance muscle size and strength. Developing               a product for which the eventual potential market is 100% of the               human population will be hard to resist.

**Some human contexts for future genetic muscle treatments**

What would be the human significance of genetic muscle treatments               becoming safe, inexpensive and thus potentially widespread in the               future? How would it change the physical (and mental) experience               of middle and old age? Preventing the decline of skeletal muscle               size and strength in older persons would probably decrease the number               of their falls and fractures, but would it also decrease the apprehensiveness               and growing timidity that frequently accompany old age? Would such               application come to blur the distinction between being “young”               and being “old”? Would there be any changes in relations               between the generations if the young ceased to be physically superior               to the old?              How might such future genetic muscle enhancement be used by persons               between the ages of say 20 and 50? Given the popularity of body-building               and fitness today, one could imagine its use to enhance those activities,               both in competitive and non-competitive settings. The commercial               and competitive pressures to use genetic muscle treatments to build               up, maintain and repair the muscles of competitive professional               athletes in all sports would be very strong. Are not pressures to               build muscles (even using anabolic steroids) already felt by student               athletes in colleges and high schools? Since athletic competition               extends down to youth soccer and Little League baseball, would there               any place to draw a line against using genetic muscle treatments?

What would be the responsibilities of parents toward their children’s               muscle development in a society where genetic muscle treatments               were safe, inexpensive and widespread? Should parents allow their               children’s muscles to develop “naturally” through               age 20? What should they do when daughter Jenny’s soccer coach               tells them she would be a stronger player if they got her genetic               muscle treatments, or that she won’t make the team unless               she gets treated? Would untreated children become stigmatized in               a society where many others had genetic muscle treatments?***Should* these biotechnological approaches be applied               to aged human muscles?**

“Sarcopenia” is currently a descriptive term for the               loss of muscle size and strength that accompanies aging. It is not               yet the name of a human disease. We will have to come to some societal               judgment about whether sarcopenia is a disease, and therefore whether               biotechnological approaches to treating it are appropriately termed               therapies.

Within American society, there is probably a diversity of views               about sarcopenia. One view would assert that loss of muscle strength               with age is part of the natural human condition, part of the natural               trajectory of human life. From this starting point, attempts to               delay this process are “unnatural” and therefore suspect.               At least, it would be argued, there is no moral requirement that               modern medicine move heaven and earth to fix this problem, particularly               by expensive, novel biotechnological means.

An alternative view would point to the fact that loss of muscle               strength on aging predisposes to falls and broken bones, major sources               of morbidity in the elderly. If we could prevent or delay such loss               of muscle strength and thereby decrease the frequency of broken               bones in the elderly, would not both individuals and society benefit?

Having agreed that sarcopenia puts a name on an important social               problem, doesn’t mean that we must be committed to muscle               gene injections as the solution. “Old-fashioned” approaches               such as diet and exercise are effective at slowing the loss of muscle               size and strength during aging. Would it be a good use of brainpower               and resources to develop genetic approaches to treating sarcopenia,               if in the end all it does is substitute for regular gym visits by               older persons for resistance strength training?              Genetic muscle treatments are being evaluated as possible therapies               for various dystrophic conditions of skeletal muscle. However, as               this paper points out, once such a technology is developed and applied               within the medical sphere, there will be substantial pressures to               use it in a variety of settings that are currently “beyond               therapy”. Genetic muscle treatments that go “beyond               therapy” are another example of an emerging bioethical dilemma…should               we apply our increasing knowledge of human biology to give future               generations of humans biological capabilities that past generations               never had? 

 

            _______________             This discussion owes much to the work                 (see references 9 and 10 below) of Professor H. Lee Sweeney and                 his colleagues at the University of Pennsylvania and elsewhere,                 and to his description and discussion of that work at the September                 2002 meeting of the President’s Council on Bioethics. 
Tzankoff, S.P., and A.H. Norris, J. Appl.                 Physiol. 43 (1977): 1001-1006
The term “sarcopenia” was                 first suggested by I.H. Rosenberg in 1989. It is derived from                 the Greek words meaning “poverty of flesh”. See I.H.                 Rosenberg. (1989) Summary Comments, Am J Clin Nutr. 50: 1231-1233.
See, for example Haslett, J.N., et al.,                 “Gene expression comparison of biopsies from Duchenne muscular                 dystrophy (DMD) and normal skeletal muscle”, Proc. Nat.                 Acad. Sci. USA, 99 (2002): 15000-15005
Zammit, P.S., and J.R. Beauchamp, “The                 skeletal muscle satellite cell: stem cell or son of stem cell?”,                 Differentiation, 68 (2001): 193-204
Owino, V., et al., “Age-related                 loss of skeletal muscle function and the ability to express the                 autocrine form of insulin-like growth factor-1 (MGF) in response                 to mechanical overload”, FEBS Letters, 505 (2001): 259-263
Brown, W.F., “A method for estimating                 the number of motor units in thenar muscles and the changes in                 motor unit count with aging”, J Neurol Neurosurg Psych,                 35 (1972): 845-852
Roubenoff, R. and V.A. Hughes, “Sarcopenia:                 Current concepts”, The Journals of Gerontology, Biological                 and Medical Sciences, Series A, 55A (2000): M716-M724
Barton-Davis, E., et al., “Viral                 mediated expression of insulin-like growth factor I blocks the                 aging-related loss of skeletal muscle function”, Proc. Nat.                 Acad. Sci. USA, 95 (1998): 15603-15607
Musaro, A., et al., "Localized Igf-1 transgene expression sustains enlargement and regeneration in senescent skeletal muscle", Nature Genetics, 27 (2001): 195-200

			 _______________ 			 -  The source for Figure 1 was                 an Internet site at http://www.sculpturegallery.com/sculpture/david.html.
- The source for Figure 2                 was http://www.schwarzenegger.com/en/athlete/index.asp?sec=athlete.
- These images are from the                 informative Internet site www.sarcopenia.com. |        |