Physiology in Perspective: The Dilemma of Muscle Weakness.

In the 5th century BCE, Socrates advised that “No man has the right to be an amateur in the matter of physical training. It is a shame for a man to grow old without seeing the beauty and strength of which his body is capable. ” Wise advice that has been repeated in many forms by those who followed Socrates, e.g., the American fitness guru Jack LaLanne, who for years promoted the health benefits of regular exercise—“So many older people, they just sit around all day long and they don’t get any exercise. Their muscles atrophy, and they lose their strength, their energy and vitality by inactivity. ” Although we all know that exercise is good for us across all ages, we don’t clearly understand how muscles atrophy and weaken with advanced age, illness, and injury. Indeed, our expert source, Wikipedia, defines muscle weakness as a lack of muscle strength—what insight. Unfortunately, our medical expertise is not much more sophisticated. In some clinical cases, we use the term myasthenia from the Greek my, meaning “muscle,” and asthenia, meaning “weakness. ” Muscle weakness can be acute, often termed fatigue, or chronic, often reflecting aging (sarcopenia), malnutrition, injury, or disease conditions. Obviously, if we lose muscle mass, our muscles become weaker, and smaller and weaker muscles are present with aging, disuse, and a variety of injury and disease conditions. For this reason, muscle force is typically normalized for muscle cross-sectional area to distinguish force loss per se from atrophy. Fortunately, through physiological research, we are now beginning to unravel the molecular mechanisms underlying muscle atrophy and force loss. This research has profound importance in a variety of acute and chronic diseases as well as with aging and injuries. The first review article in this issue of Physiology addresses the molecular mechanisms underlying muscle atrophy. Skeletal muscle atrophy has many causes, including aging, malnutrition, muscle disuse, and serious illnesses or injuries. Loss of muscle mass can cause weakness, fatigue, reduced activity, disorders in whole-body metabolism, delayed recovery from acute illness and injury, and increased morbidity and mortality resulting from falls, chronic disease, extended hospital stays, or loss of independent living. Despite its broad clinical impact, skeletal muscle atrophy still lacks a pharmacological therapy and remains poorly understood at the molecular level. In their review (2), Ebert et al. discuss recently identified molecular mechanisms of muscle atrophy. Potential therapies resulting from research on skeletal muscle atrophy can improve both health and quality of life by elucidating new ways to preserve muscle mass and strength during illness, injury, and aging. Protein kinase A (PKA) is activated by the binding of cyclic adenosine monophosphate (cAMP), and cAMP/PKA signaling modulates contractile, metabolic, and transcriptional cellular responses. This neurohormonal regulation of cardiovascular functions is the target of numerous current therapeutics for the treatment of heart disease. In their review (1), Bers and colleagues discuss a recent discovery that the pleiotropic effects of cAMP/PKA signaling are highly localized in subcellular compartments at a nanometer scale and are uniquely regulated to deliver distinct signals to different nanodomains. This localized control of cAMP/PKA signaling allows fine tuning for optimal physiological responses, although disruption of this local cAMP/PKA signaling can contribute to disease. Real-time Förster (or fluorescence) resonance energy transfer (FRET) imaging using genetically encoded reporters of cAMP levels and PKA activity has been instrumental in defining this compartmentalized signaling. Recent studies using nanodomain-targeted FRET reporters revealed a previously unsuspected sub-microscopic heterogeneity of intracellular cAMP and PKA signals, and provided evidence that the physiologically relevant cAMP is confined to nano-domains immediately surrounding effector-target complexes. These findings subvert the classical notion of diffusive cAMP signaling and provide a new framework for the development of targeted therapeutic approaches. A detailed understanding of cAMP/PKA subcellular nanodomains may pave the way for precision medicine strategies to target local cAMP pools, rather than global intracellular cAMP levels, to achieve greater therapeutic efficacy and specificity. Ratiology refers to the study, application, and interpretation of ratios as they relate to data collection for the purpose of diagnosis and clinical research. Cardiovascular investigations often involve ratio-based metrics or differences: e.g., evaluation of ventricular function, assessment of coronary flow, optimization of ventriculo-arterial coupling, and pressure-derived assessment of arterial vessel stiffness. In their review (3), Kerkoff et al. discuss how the current practice of using derived metrics rather than interpreting the original data may be a misleading method of analyzing the cardiovascular system. In fact, it is unclear how much physiological content is contained within a ratio. Although the acceptance of uncalibrated data is a practical convenience, the results are incomplete. Interpretation of the primary data, which would require calculation and interpretation of the data by physiologists should be considered, since it will permit more personalized diagnosis and treatment. The carotid body has recently resurfaced as a potentially potent target organ for treating a wide range of human diseases such as heart failure, high blood pressure, sleep apnea, and diabetes, among others. In their review (5), Zera et al. consider the intricate connectivity between the carotid body and the brain, taking a novel high-resolution look inside this tiny organ to see whether there are separate lines of communication between subpopulations of carotid body cells and the brain that mediate distinct reflex functions. What is intriguing, and clinically most relevant, is the discovery that these separate lines of communication appear to use different transmitter-receptor mechanisms. In other words, they are chemically encoded. This is important since it potentially allows for targeted PHYSIOLOGY IN PERSPECTIVE Gary C. Sieck (Editor-in-Chief) Mayo Clinic, Rochester, Minnesota PHYSIOLOGY 34: 230–231, 2019.