Mechanistic links between oxidative stress and disuse muscle atrophy

Abstract

Long periods of skeletal muscle inactivity promote a loss of muscle protein resulting in fiber atrophy. This disuse-induced muscle atrophy results from decreased protein synthesis and increased protein degradation. Recent studies have increased our insight into this complicated process, and evidence indicates that disturbed redox signaling is an important regulator of cell signaling pathways that control both protein synthesis and proteolysis in skeletal muscle. The objective of this review is to outline the role that reactive oxygen species play in the regulation of inactivity-induced skeletal muscle atrophy. Specifically, this report will provide an overview of experimental models used to investigate disuse muscle atrophy and will also highlight the intracellular sources of reactive oxygen species and reactive nitrogen species in inactive skeletal muscle. We then will provide a detailed discussion of the evidence that links oxidants to the cell signaling pathways that control both protein synthesis and degradation. Finally, by presenting unresolved issues related to oxidative stress and muscle atrophy, we hope that this review will serve as a stimulus for new research in this exciting field.

FIG. 1.

Human conditions that promote skeletal muscle atrophy and the corresponding animal models that are used to investigate them.

FIG. 2.

Simplified diagram illustrating pathways capable of producing superoxide (O₂^-) in skeletal muscle during periods of disuse. Candidates for the production of reactive oxygen include NADPH oxidase, xanthine oxidase, and muscle mitochondria.

FIG. 3.

Reactive oxygen species depress global protein synthesis in cells. A potential mechanism to explain the impact of ROS on protein synthesis is that high levels of ROS can inhibit translation at the level of initiation, in part, by reducing phosphorylation of the eIF4E repressor protein, 4E-BP1. See text for more details.

FIG. 4.

Oxidative stress can promote muscle protein breakdown in three major ways: 1) Oxidative stress increases the gene expression of key proteins involved in autophagy, calpain, and the proteasome system of proteolysis; 2) Cellular oxidative stress can activate both calpain and caspase-3; 3) Oxidants modify the structure of myofibrillar proteins and enhance their susceptibility to proteolytic processing.

FIG. 5.

Steps leading to autophagy and the key autophagy proteins involved in each step. Note that ROS has been shown to increase the expression of Atg6 (Beclin-1) and cathepsins B,D, and L in cell culture.

FIG. 6.

Some of the key components of the 26S proteasome system of proteolysis. The total proteasome complex (26S) is comprised of a core proteasome subunit (20S) coupled with a regulatory complex (19S) connected to each end of the 20S core. The binding of ubiquitin to protein substrates is a three-step process that initially requires the ubiquitin-activating enzyme (E1), a variety of ubiquitin-conjugating enzymes (E2s), and specialized protein ligases (E3s) that recognize specific protein substrates. See text for more details.