Molecular Mechanisms Underlying Skeletal Muscle Weakness in Human Cancer: Reduced Myosin-Actin Cross-Bridge Formation and Kinetics

摘要

PHYSICAL FUNCTION DETERIORATES substantially following a diagnosis of cancer (3, 48), and patients view this decline as one of the most distressing side effects of the disease, more so than classic side effects such as pain, nausea, and vomiting (13, 60). Functional disability can be the impetus for dose reduction or cessation of anticancer treatments and predicts chemotherapy toxicity and survival (12, 30, 33, 39). Our current understanding of the factors contributing to reduced functional capacity in patients with cancer is, however, severely limited. Physiological changes that occur within the skeletal muscle of patients with cancer can contribute to functional deterioration and physical disability. The most common adaptations believed to promote functional impairment are muscle atrophy, reduced cardiorespiratory fitness, and skeletal muscle weakness (20, 32, 54). The vast majority of studies of muscle biology in cancer have focused on signal transduction mechanisms underlying skeletal muscle atrophy (20). Understanding quantitative alterations in skeletal muscle and their mechanisms is important because they have relevance for physical function (38) and clinical outcome (18), but functional deficits persist after controlling for muscle atrophy (34, 54), and there is compelling evidence to suggest that cancer has a unique effect on the intrinsic functionality of muscle (22). In other words, a substantial proportion of the decline in physical capacity is likely explained by reductions in function per unit tissue size. Skeletal muscle contractile dysfunction has received minimal attention as a precipitant of functional changes in patients with cancer (54, 61), with the majority of studies being focused on cardiorespiratory fitness (32). However, reduced skeletal muscle contractile function is a strong predictor of decreased physical functioning in common daily activities (49) in many studies rivaling or exceeding the contribution attributed to diminished aerobic capacity (8, 51). Additionally, at a more fundamental level, the properties of the contractile elements (i.e., myofilament proteins) determine the functional character of skeletal muscle and, correspondingly, whole-body performance (24, 28, 29). As the end effectors of muscle contraction, myofilament mechanical properties necessarily set limits for muscle functionality (10). To date, no studies have evaluated the effects of cancer on myofilament protein content, structure, or functionality in humans. The goal of this study was to examine the effect of cancer on skeletal muscle contractile function at the molecular, cellular, whole-muscle, and whole-body levels. To accomplish this objective, we evaluated whole-body and whole-muscle performance using standard functional assessments and cellular/molecular structure and function on intact and chemically skinned fibers from the vastus lateralis muscle in patients with cancer and controls. Because cancer-related functional deficits are suggested to be more common in patients experiencing weight loss and during treatment (i.e., chemo/radiotherapy), we included both cachectic and noncachectic patients and patients undergoing cancer treatment. In this context, our cohort does not permit us to address the unique effect of cancer per se, but instead encompasses the effects of the disease, its treatment, and disease- and treatment-related sequelae such as weight loss. However, when discussing our findings, we refer to the effects of cancer for simplicity.