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.

Keywords: disuse muscle atrophy; mechanical unloading; molecular and cellular pathways; protein degradation; protein synthesis; therapeutic countermeasures.

Figure 1

Diagrammatic representation of the protein synthesis signaling mechanisms responsible of skeletal muscle atrophy following mechanical unloading. IGF-1, insulin-like growth factor-1; PI3K, phosphatidylinositol 3 kinase; Akt/PKB, protein kinase B; FAK, focal adhesion kinase; mTORC1, mechanistic target of rapamycin in complex 1; REDD, regulated in DNA damage and development; GSK-3β, glycogen synthase kinase 3β; S6K1, 70 kDa ribosomal protein S6 kinase 1; 4E-BP1, eIF4E binding protein 1; ROS, reactive oxygen species. The black arrow and inhibition symbol show the association of molecules under loading condition, red arrow shows the up/down-regulation of molecules under unloading condition. For more details see text.

Figure 2

Diagrammatic representation of the protein degradation signaling mechanisms responsible of skeletal muscle atrophy following mechanical unloading. IGF-1, insulin-like growth factor-1; PI3K, phosphatidylinositol 3 kinase; Akt/PKB, protein kinase B; FOXO, forkhead family of transcription factors; NF-κB, nuclear factor kappa-B; MuRF1, muscle ring finger 1; MAFbx, muscle atrophy F-box 1; ROS, reactive oxygen species. The black arrow and inhibition symbol show the association of molecules under loading condition, red arrow shows the up/down-regulation of molecules under unloading condition. For more details see text.