Skeletal Muscle Mitochondrial Density, Gene Expression, and Enzyme Activities in Human Heart Failure: Minimal Effects of the Disease and Resistance Training
IMPAIRED SKELETAL MUSCLE ENERGETICS in heart failure (HF) patients (32) may contribute to physical disability and metabolic dysfunction. Decreased skeletal muscle oxidative capacity (63), secondary to reduced mitochondrial density (12, 13) and/or function (10, 36, 52), may contribute to exercise intolerance, the hallmark symptom of HF. Moreover, as mitochondrial dysfunction is associated with fiber atrophy (7), impaired energetics may reduce physical function by promoting muscle wasting and, in turn, weakness (21). Because mitochondrial dysfunction has been implicated in the pathophysiology of diabetes (41), alterations in mitochondrial content and/or function could also contribute to the high prevalence of insulin resistance in the HF population (53), which could provoke deleterious protein metabolic effects that predispose to atrophy (56). Knowledge of the unique effects of HF on mitochondrial biology is limited, because nearly all studies have failed to account for several factors that accompany the syndrome of HF and can alter mitochondrial structure and function, the most notable being muscle disuse (55) and hospitalization. Studies that have attempted to control for muscle disuse in the HF population by recruitment of sedentary controls have found minimal effects of HF on mitochondrial function (8, 33, 68). There are, however, deficiencies in mitochondrial biology that persist following control for muscle disuse [e.g., mitochondrial and cytosolic enzyme activity (33)] and other aspects of the mitochondrial myopathy of HF that have not been compared between patients and controls matched for activity level. Thus it is unclear whether deficits in mitochondrial content or aspects of mitochondrial function are related to the HF syndrome per se or are a consequence of muscle disuse and/or other disease-related factors (47). If muscle disuse contributes to deficiencies in mitochondrial structure and function in HF (8, 33, 68), exercise interventions should improve muscle energetics. In support of this notion, aerobic exercise training improves physical function in HF patients (11), and some portion of its beneficial effect is likely related to increased skeletal muscle mitochondrial content and/or function (20, 71). Despite the many benefits of aerobic exercise training, it is generally not considered an effective intervention to increase muscle size or strength (24,26). Exercise that provokes muscle anabolism, such as resistance training, may need to be incorporated into standard, aerobic exercise-based rehabilitation regimens to more completely address the range of morphological and functional alterations in skeletal muscle in HF that limit physical function. Indeed, studies that have employed a combination of aerobic- and resistance-training programs in HF patients have shown improved aerobic fitness and muscle strength (4, 14, 67) accompanied by improved mitochondrial function (67). However, it is unclear whether the resistance-training component of the program contributes to improvements in mitochondrial biology or whether these improvements are related solely to the aerobic component. Conventional wisdom, which has been gleaned largely from studies in younger individuals, holds that resistance training has minimal or deleterious effects on skeletal muscle mitochondrial content or function (22, 54). Recent studies, however, have challenged this notion (44, 62). In elderly individuals, in particular, beneficial effects of resistance training on mitochondrial content, enzyme activity, and the expression of genes regulating mitochondrial size and function (23, 31, 43), as well as improvements in aerobic fitness (15), have been found. In HF patients and controls, resistance exercise training improves physical function (1, 49), including activities that are believed to be dependent on aerobic metabolism, such as walking endurance (1, 42, 45, 49), suggesting that this training modality has salutary effects on muscle endurance. In HF patients, resistance training has been reported to increase aerobic fitness (14, 27), along with mitochondrial enzyme activity (45), suggesting that this training modality may potentiate muscle endurance through effects on mitochondrial biology. However, a systematic evaluation of whether resistance training has beneficial effects on mitochondrial structure, enzyme activity, and gene expression in HF patients has not been undertaken. The goals of this study were twofold. First, we sought to evaluate the unique effect of HF on skeletal muscle mitochondrial content, gene expression, and enzyme activity. To accomplish this objective, we geared our recruitment strategies to mitigate the effects of chronic muscle disuse (55) and other aspects of the HF syndrome that could modify mitochondrial biology. Second, we sought to examine whether resistance training has beneficial effects on these mitochondrial properties. To accomplish this aim, these parameters were reassessed in the cohort after an 18-wk high-intensity, resistance exercise-training program
