Redox control of skeletal muscle atrophy

Abstract

Skeletal muscles comprise the largest organ system in the body and play an essential role in body movement, breathing, and glucose homeostasis. Skeletal muscle is also an important endocrine organ that contributes to the health of numerous body organs. Therefore, maintaining healthy skeletal muscles is important to support overall health of the body. Prolonged periods of muscle inactivity (e.g., bed rest or limb immobilization) or chronic inflammatory diseases (i.e., cancer, kidney failure, etc.) result in skeletal muscle atrophy. An excessive loss of muscle mass is associated with a poor prognosis in several diseases and significant muscle weakness impairs the quality of life. The skeletal muscle atrophy that occurs in response to inflammatory diseases or prolonged inactivity is often associated with both oxidative and nitrosative stress. In this report, we critically review the experimental evidence that provides support for a causative link between oxidants and muscle atrophy. More specifically, this review will debate the sources of oxidant production in skeletal muscle undergoing atrophy as well as provide a detailed discussion on how reactive oxygen species and reactive nitrogen species modulate the signaling pathways that regulate both protein synthesis and protein breakdown.

Keywords: Antioxidants; Muscle protein synthesis; Oxidants; Oxidative stress; Proteolysis; Reactive nitrogen species; Reactive oxygen species.

Figure 1

Schematic of the Akt/mTORC1 signaling pathway leading to accelerated translation and increased protein synthesis. Note that both ROS and RNS have been shown to impede one or more steps leading to a decrease in muscle protein synthesis. See text for details.

Figure 2

Illustration of the steps leading to autophagy. Autophagy progresses during a five step process: 1) Induction; 2) Expansion; 3) Completion of autophagosome; 4) Autophagosome fuses with lysosome; and 5) Degradation of proteins and organelles. As discussed in the text, both ROS and RNS have the potential to accelerate autophagy flux. See text for details.

Figure 3

Simplified diagram illustrating the role of FOXO3 in promoting gene expression of both muscle specific E3 ligases (i.e., atrogin 1 and MuRF1) and autophagy genes. Note that both ROS and RNS have the potential to accelerate protein breakdown via the proteasome and autophagy pathway. See text for more details.

Figure 4

Simplistic overview of the role that ROS plays in promoting an increase in intracellular calcium and calpain activation in skeletal muscle. See text for more details.

Figure 5

Summary of the role that ROS/RNS play in activation of caspase-3 in skeletal muscle. Note that ROS can promote caspase-3 activation via both an intrinsic pathway (mitochondrial) or extrinsic pathway involving the activation of caspase-12. See text for more details.