Muscle Atrophy Induced by Mechanical Unloading: Mechanisms and Potential Countermeasures

Abstract

Prolonged periods of skeletal muscle inactivity or mechanical unloading (bed rest, hindlimb unloading, immobilization, spaceflight and reduced step) can result in a significant loss of musculoskeletal mass, size and strength which ultimately lead to muscle atrophy. With advancement in understanding of the molecular and cellular mechanisms involved in disuse skeletal muscle atrophy, several different signaling pathways have been studied to understand their regulatory role in this process. However, substantial gaps exist in our understanding of the regulatory mechanisms involved, as well as their functional significance. This review aims to update the current state of knowledge and the underlying cellular mechanisms related to skeletal muscle loss during a variety of unloading conditions, both in humans and animals. Recent advancements in understanding of cellular and molecular mechanisms, including IGF1-Akt-mTOR, MuRF1/MAFbx, FOXO, and potential triggers of disuse atrophy, such as calcium overload and ROS overproduction, as well as their role in skeletal muscle protein adaptation to disuse is emphasized. We have also elaborated potential therapeutic countermeasures that have shown promising results in preventing and restoring disuse-induced muscle loss. Finally, identified are the key challenges in this field as well as some future prospectives.

Muscle unloading: A comparison between spaceflight and ground‐based models

“…Further, the potential contribution of these two genes to inactivity‐induced muscle atrophy is evident by the fact that the mice deficient of these genes are resistant to atrophy . Similar findings have been reported in humans after bed rest and unilateral limb immobilization . The expression of these two E3 ligases is primarily regulated by FOXO transcription factors .…”

“…Muscle protein synthesis is stimulated by the activation of mammalian target of rapamycin (mTOR) pathway, a key regulator of translation initiation and its downstream targets S6 kinase‐1 (S6K1) and 4E binding protein 1 (4E‐BP1). It is, thus, not surprising that muscle unloading is associated with decreased activation of mTOR pathway (Figure ) and reduced phosphorylation of AkT, S6K1 and 4E‐BP1 . Mechanical unloading also causes altered binding of 4E‐BP1 and Eif4e, and reduced phosphorylation of GSK3β, which contributes to reduced protein synthesis.…”

“…Detailed mechanisms of disuse atrophy can be found in some excellent reviews elsewhere in the literature . Here, we present a brief overview of the mechanisms leading to disuse atrophy.…”

“…However, during unloading, dephosphorylated FOXO translocate to the nucleus and upregulated genes related to muscle proteins breakdown . Several reports show that the protein and mRNA expression of FOXO is upregulated during disuse atrophy . Moreover, overexpression of FOXO induces muscle atrophy while suppression of FOXO attenuates disuse muscle atrophy .…”

“…Here, we will summarize findings on some important countermeasures to muscle loss in space. Readers are encouraged to read some excellent reviews on this topic elsewhere …”