Mitochondrial Bioenergetics and Turnover during Chronic Muscle Disuse

Abstract

Periods of muscle disuse promote marked mitochondrial alterations that contribute to the impaired metabolic health and degree of atrophy in the muscle. Thus, understanding the molecular underpinnings of muscle mitochondrial decline with prolonged inactivity is of considerable interest. There are translational applications to patients subjected to limb immobilization following injury, illness-induced bed rest, neuropathies, and even microgravity. Studies in these patients, as well as on various pre-clinical rodent models have elucidated the pathways involved in mitochondrial quality control, such as mitochondrial biogenesis, mitophagy, fission and fusion, and the corresponding mitochondrial derangements that underlie the muscle atrophy that ensues from inactivity. Defective organelles display altered respiratory function concurrent with increased accumulation of reactive oxygen species, which exacerbate myofiber atrophy via degradative pathways. The preservation of muscle quality and function is critical for maintaining mobility throughout the lifespan, and for the prevention of inactivity-related diseases. Exercise training is effective in preserving muscle mass by promoting favourable mitochondrial adaptations that offset the mitochondrial dysfunction, which contributes to the declines in muscle and whole-body metabolic health. This highlights the need for further investigation of the mechanisms in which mitochondria contribute to disuse-induced atrophy, as well as the specific molecular targets that can be exploited therapeutically.

Keywords: apoptosis; autophagy; mitochondrial biogenesis; mitochondrial quality control; mitophagy; muscle disuse; reactive oxygen species; skeletal muscle atrophy.

Figure 1

Disuse-induced mitochondrial derangements contribute to skeletal muscle fiber atrophy. (A) Atrophic regions of muscle fibers brought about following periods of prolonged muscle inactivity display marked alterations in mitochondrial morphology and function which can be visualized microscopically and have been determined experimentally. (B) Both subsarcolemmal (SS; yellow arrow) and intermyofibrillar (IMF) mitochondrial populations appear fragmented, with irregular shapes and unusual cristae formation indicative of dysfunctional organelles (green mitochondria). Defects in the mitochondrial turnover machinery contribute to the appearance of undegraded vacuoles, termed lipofuscin (blue arrows), which contribute to the irregularities within the sarcomere. (C) The absence of muscle contraction results in a decrease in the ADP supply, resulting in lower respiratory rates and an enhanced proton motive force (Δψ), thus promoting the creation of reactive oxygen species (ROS) in the form of superoxides (O₂^•−) and H₂O₂. Mitochondrial and cytosolic antioxidants neutralize superoxides, first via conversion to H₂O₂ by superoxide dismutases SOD1 and SOD2, then to water by antioxidant enzymes such as catalase or glutathione. As mitochondrial antioxidants are downregulated during muscle disuse, ROS accumulate in muscle mitochondria triggering the activation of degradation pathways. (D) Mitochondrial quality is maintained by the mitophagy machinery to selectively envelop dysfunctional organelles and delivers them to the lysosome for recycling. With chronic disuse, the process is impaired, leading to the accumulation of undegraded dysfunctional mitochondria. (E) In addition to this impaired turnover, activation of signaling kinases is reduced, leading to a diminished drive for mitochondrial biogenesis via PGC-1α, and promoting the expression of atrogenes, such as MuRF1 and atrogin1 that enhance protein degradation. (F) A consequence of the impaired mitochondrial quality control and chronic organelle dysfunction is the formation and opening of the mitochondrial permeability transition pore (mPTP), and subsequent release of pro-apoptotic factors such as AIF, Cytochrome c and SMAC, which lead to DNA fragmentation. (G) Collectively, these derangements contribute to enhanced protein degradation relative to protein synthesis, thus, exacerbating muscle atrophy. (H) Regular endurance exercise reverses many of the mitochondrial defects that are observed with chronic inactivity, and therefore is capable of preventing, diminishing or reversing disuse-induced muscle atrophy.