Introduction to symposium proceedings: the emerging interplay among muscle mitochondrial function, nutrition, and disease.

Mitochondria are the cellular oxidative powerhouse long recognized for their role in the conversion of fat and carbohydrate fuels intotheATPneededforcell function.Fortyyearsago,JohnHolloszy made a seminal discovery that mitochondrial size, number, and function increase in skeletal muscle in response to endurance exercise training (1). Since then, mitochondrial biogenesis has been recognized to be a key component of adaptation to exercise. Conversely, there is now a growing appreciation, which has developed within the past few years, for how reduced muscle mitochondrial content and function are common features of 3 prevalent conditions in current society: obesity, diabetes, and aging. This suggests that mitochondria may play a central role in the interaction between diet, lifestyle, and disease. On 5 April 2008, a symposium entitled, ‘‘The Emerging Interplay among Muscle Mitochondrial function, Nutrition, and Disease’’ was held as part of the American Society for Nutrition’s scientific program at Experimental Biology 2008 in San Diego. The purpose of the symposium was to highlight recent findings on the role of mitochondria in obesity, insulin resistance, and aging. Lawrence Spriet provided an update on the regulation of fat oxidation in muscle and how it is influenced by obesity. Fat oxidation is reduced in obese individuals when measured at the whole-body level or in whole-cell muscle preparations. However, Spriet and his colleagues demonstrated that the reduced fat oxidation is mainly attributable to lower mitochondria content rather than a mitochondrial defect. In their studies, isolated mitochondria from lean and obese subjects oxidized fatty acids at similar rates (2). They found, however, that expression of some of the transcription factors that control mitochondria biogenesis may be regulated differentially in obesity, which may account for the lower mitochondrial protein content (3). Kitt Petersen addressed the issue of how skeletal muscle mitochondrial function may be related to insulin resistance. Petersen et al have reported that the rate of mitochondrial oxidative phosphorylation as well as insulin sensitivity are reduced in elderly people (4). They also found that mitochondrial substrate oxidation and ATP synthesis were reduced in insulin-resistant young adults compared with age-matched people without insulin resistance (5, 6). In both of these cases, mitochondrial ATP synthesis and insulin sensitivity were inversely related to intramuscular lipid content. This led to a proposal that mitochondrial dysfunction may be closely associated with, and perhaps even precede, the development of insulin resistance. This could occur in association intracellular fat accumulation secondary to the disruption in fuel oxidation. John Holloszy presented another perspective on the connection between insulin resistance and mitochondrial function and the role of dietary fat. Holloszy pointed out that mitochondrial fuel oxidative capacity exceeds the energy needs of skeletal muscle while at rest, during moderate intensity activity, and for insulinmediated glucose uptake, even in subjects with obesity and insulin resistance. His group has used a high-fat diet model to show that muscle insulin resistance and mitochondrial content are not directly linked. In response to high fatty acid availability, insulin resistance to glucose uptake occurred rapidly but was followed by slower transcription factor changes that ultimately caused upregulation of the fat oxidation pathways in mitochondria (7, 8). Thus, insulin resistance was found to coexist with mitochondrial biogenesis. This type of evidence has been used to suggest that the reduced mitochondrial content in obesity and diabetes may be secondary to insulin resistance or physical inactivity but is not responsible for insulin resistance in these conditions. Finally, K Sreekumaran Nair summarized recent work on how mitochondrial function is affected by aging and exercise. In sedentary people, muscle content of mitochondrial gene transcripts, proteins, and DNA were shown to decrease with age (9–11); however, many of these changes appear to be closely related to lifestyle. Unlike their sedentary peers, older people who performed frequent endurance exercise training over several years showed little or no difference in mitochondrial function or biogenesis markers compared with young trained persons (9). Furthermore, when previously sedentary older people completed a standardized endurance training program, responses in muscle mitochondria were similar to those of sedentary young people who performed the same training program (11). The main conclusion that can be drawn from this symposium is that muscle mitochondrial function, defined as the ability to perform fuel oxidation and generate ATP, is typically reduced in conditions of obesity, insulin resistance, and advanced age. Whether this represents an intrinsic dysfunction of mitochondria or a reduction in mitochondrial content may vary with specific conditions, but for the areas covered here, mitochondrial content seems to be the primary deficit. Given these findings, the next challenge should be to address ways to prevent or reverse the