Molecular mechanisms of oxidative stress in aging muscle

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DESCRIPTION (provided by applicant): With age we lose muscle mass at approximately 1-2% per year past the age of 50. This age-related muscle atrophy, termed sarcopenia, is relatively poorly understood, impacts the severity of frailty, and has significant effects on individual health and quality of life. While the specific mechanisms underlying sarcopenia are unknown, energy deficits in aging muscle have been strongly implicated as precursors to muscle atrophy and apoptotic cell death, suggesting that mitochondrial dysfunction may play a significant role in the progression of sarcopenia. Previous studies have shown decreased mitochondrial oxidative functional capacity with age, which was associated with increased oxidant production in mitochondrial complex I and complex III. However, characterization of age-related changes to skeletal muscle mitochondria has been complicated by the realization that two distinct populations of mitochondria exist: interfibrillar mitochondria (IFM), which are found in parallel rows between the myofibrils, and subsarcolemmal mitochondria (SSM), which are located beneath the plasma membrane. IFM are likely the primary source of ATP during muscle contraction, and we believe they are therefore more likely to accumulate oxidative damage with age. Our central hypothesis is that IFM exhibits a greater free radical leak in complex I and III and oxidative damage, and that this is responsible for increased mitochondrial dysfunction, skeletal muscle atrophy and decreased contractile function, all of which could be amplified in type II muscle compared with type I muscle. In the proposed experiments, we will obtain young, mid-aged and old rats, determine skeletal muscle contractile function, apoptosis and the extent of sarcopenia in type I and type II muscle, and we will isolate IFM and SSM from both fiber types and measure key parameters of bioenergetics. In a second series of experiments, we will examine the same factors and variables, but with addition of two well-characterized interventions that have been shown to extend life span: calorie restriction and life-long wheel running, to determine the mechanisms by which these interventions significantly ameliorate age-related oxidative damage, mitochondrial dysfunction and muscle loss. This could provide evidence for the mechanisms underlying sarcopenia, and may also provide the first direct evidence that mitochondrial dysfunction has a negative impact on muscle cell function and contractility.