Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

Abstract

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

Keywords: calpain; muscle atrophy; oxidative stress; protein synthesis; proteolysis; reactive oxygen species.

Figure 1

Dysfunctional mitochondria display a disrupted morphology that appears swollen and fragmented compared to healthy mitochondria. These alterations coincide with an impaired respiratory capacity (e.g., decreased mitochondrial complex activity) that results in diminished ATP production, increased mitochondrial ROS emissions, and the release of mitochondria-derived proapoptotic factors.

Figure 2

Mitochondrial dysfunction arising from conditions of prolonged muscle inactivity, aging, chemotherapy, cancer, and sepsis, resulting in muscle wasting. Decreased respiratory capacity decreases ATP content and activates AMPK signaling. Increased ROS emissions activate the major proteolytic pathways and inactivates muscle protein synthesis pathways. The release of mitochondrial-derived proapoptotic factors activates caspase-3 and mediates myonuclear apoptosis.