Chronic disease dramatically increases the likelihood that an individual will become physically disabled. The mechanism(s) whereby chronic diseases promote the loss of skeletal muscle size and function to promote physical disability, however, is unclear. Our laboratory has focused on the effects of chronic heart failure on skeletal muscle structure, function and metabolism. Early studies evaluated the mechanisms underlying skeletal muscle atrophy in heart failure in both humans and animal models; specifically, whether alterations in skeletal muscle protein synthesis, breakdown and/or apoptosis contribute to muscle wasting. An unexpected observation in these studies was that the contractile protein myosin was selectively depleted from patients with heart failure (Toth et al. 2005, 2006). Our observations occurred at the time when other laboratories were reporting similar effects in humans and animal models with aging, cancer and muscle disuse. We received funding to extend our initial observations in the whole muscle to the single fiber level in collaboration with colleagues in the Department of Molecular Physiology and Biophysics.
In these studies, we compared heart failure patients to controls who were matched for age, sex, muscle size and physical activity level to isolate the unique effect of the heart failure syndrome. At the whole body level, heart failure patients' ability to perform necessary activities of daily living was significantly reduced compared to controls and this impairment was related to reduced muscle strength (Savage et al. 2011). Reduced whole muscle strength, in turn, was evident after adjustment for differences in muscle size (Toth et al. 2010), suggesting an intrinsic defect in the functional capacity of muscle. This intrinsic contractile dysfunction was confirmed at the single fiber level, where biochemical and mechanical assessments showed a loss of myosin and suggested that these decrements may contribute to muscle weakness (Miller et al. 2009). Further experiments evaluating the mechanisms underlying the loss of myosin showed no effect of heart failure on myosin gene transcription or myosin proteolysis (Miller et al. 2009), although we have shown that reduced myosin protein content is related to diminished activation of certain anabolic signaling molecules (Toth et al. 2011). Thus, the mechanisms underlying the loss of single fiber myosin protein content in heart failure remain unclear. In addition to these measurements, with the help of our collaborators, we have been able to apply the powerful technique of sinusoidal analysis to human skeletal muscle fibers for the first time. This technique enables us to examine the effect of heart failure on muscle function at the level of the myosin-actin cross-bridge. These studies revealed that heart failure decreases cross-bridge kinetics, due to an increase in the time that myosin stays attached to actin (Miller et al. 2010). Taken together, these observations provide potential molecular explanations for functional alterations in skeletal muscle in human heart failure.
In addition, we have evaluated the effects of 4 months of resistance exercise training to remediate these defects. Resistance training improves skeletal muscle strength and performance in heart failure patients (Savage et al. 2011) and these improvements are likely not related to improvements in aerobic fitness and/or mitochondrial function (Toth et al. 2012). Instead, we believe that the functional benefits of training are explained, in part, by improvements in myofilament protein function evident at the cellular and molecular levels (Toth et al. 2011). Of note, these studies also uncovered previously unidentified modifications in molecular structure and function that may explain more generally the favorable effects resistance training on muscle function (Toth et al. 2011) . Thus, therapies targeted towards specific molecular defects (ie, myosin/myofilament structure and function) may be effective in reducing heart failure-associated physical disability.
Last modified June 12 2012 03:03 PM