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.
Highlights
The adaptability of skeletal muscle to various external stimuli has profound ramifications for overall health
This is revealed by an increased respiratory control ratio (RCR) by 30% in the diaphragms of exercised animals that had previously undergone mechanical ventilation, representing a substantial improvement in the disuseinduced reduction in the RCR, and protection against mitochondrial uncoupling [127,128] The decline in mitochondrial energetics and content that occurs during disuse can be reversed with reinstated ambulation after periods of inactivity
Mitochondria play a role in the regulation of muscle mass and quality via retrograde signaling to the nucleus involving reactive oxygen species (ROS), energy deficits and apoptosis
Summary
The adaptability of skeletal muscle to various external stimuli has profound ramifications for overall health. In the absence of disease, skeletal muscle disuse may be brought about by chronic sedentarism, periods of immobilization due to injury, bed rest as result of illness, or for a select few, exposure to microgravity In these cases, muscle atrophy may occur in the affected limb or more broadly throughout the body, creating functional and metabolic derangements in the affected tissue. The additional benefit of dry-immersion bed rest is the higher rate and greater extent at which neuromuscular adaptations are achieved, compared to traditional bed rest [28] Both bed rest and limb immobilization studies allow effective countermeasures to be tested, in order to prevent, offset, or reverse the decline in muscle observed with disuse, while providing a relevant model of the wasting associated with diseases and aging. Samples derived from these patients, scarce, allow for direct study of the myopathy that makes these subjects unable to return to normal, unsupported ventilation [31,32]
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