Our work in diseased populations has primarily focused on patients with chronic heart failure. More recently, we have evaluated the effects of cancer on skeletal muscle structure and function..
Heart failure patients experience high rates of physical disability. Historically, cardiac insufficiency was cited as the cause of diminished physical capacity, but studies in the last three decades have clearly shown that alterations in skeletal muscle contribute to functional disability. The mechanism(s) whereby heart failure alters 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. An unexpected observation in these studies was that the contractile protein myosin was 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 extended our initial observations in the whole muscle to the single fiber level. 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). In addition, we applied the technique of sinusoidal analysis to human skeletal muscle fibers for the first time to enable examination of 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). We would predict that this kinetic modification would reduce contractile velocity, which, in turn, could contribute to reduced muscle power output (Toth 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 shown that 4 months of resistance exercise training training improves skeletal muscle strength and performance in heart failure patients (Savage et al. 2011) and these improvements are not accompanied by alterations in either aerobic fitness 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. 2012). 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 improving myofilament structure and function, such as resistance training, may be effective in reducing heart failure-associated physical disability. Thus, rehabilitative strategies to improve functionality and quality of life in heart failure patients should incorporate some type of resistive training.
Cancer patients also experience high rates of physical disability, which impacts treatment decisions, quality of life and clinical outcomes. Adaptations in skeletal muscle may contribute to reduced physical capacity and these greater rates of disability. The vast majority of studies of muscle biology in cancer have focused on signal transduction pathways underlying muscle atrophy, but there is compelling evidence that cancer impairs skeletal muscle function after factoring in the loss of muscle mass. Skeletal muscle contractile dyfunction, however, has received minimal attention as a precipitant of disability. To characterize skeletal muscle adaptations to cancer in humans, we evaluated skeletal muscle structure and contractile function at the molecular, cellular, whole muscle and whole body level in cancer patients and non-diseased controls (Toth et al. 2013). Cancer patients showed reduction in knee extensor isometric torque after adjustment for muscle mass, which was strongly related to diminished power output during a walking endurance test. At the cellular level, single fiber isometric tension was reduced in myosin heavy chain (MHC) IIA fibers in cancer patients, due to a reduction in the number of strongly-bound cross-bridges. In MHC I fibers, myosin-actin cross-bridge kinetics were reduced in patients, as evidenced by an increase in myosin attachment time, which was related to their reduced mitochondrial density in cancer patients. Collectively, our results suggest reductions in myofilament protein function as a potential molecular mechanism contributing to muscle weakness and physical disability in human cancer. We are currently seeking funding to more completely characterize these skeletal muscle adaptations, their contribution to cancer-related disability and the utility of intervevntions to forestall muscle dysfunction and functional disability.
Last modified November 25 2013 09:14 AM