Molecular events and signalling pathways involved in skeletal muscle disuse-induced atrophy and the impact of countermeasures

Abstract

Disuse-induced skeletal muscle atrophy occurs following chronic periods of inactivity such as those involving prolonged bed rest, trauma and microgravity environments. Deconditioning of skeletal muscle is mainly characterized by a loss of muscle mass, decreased fibre cross-sectional area, reduced force, increased fatigability, increased insulin resistance and transitions in fibre types. A description of the role of specific transcriptional mechanisms contributing to muscle atrophy by altering gene expression during muscle disuse has recently emerged and focused primarily on short period of inactivity. A better understanding of the transduction pathways involved in activation of proteolytic and apoptotic pathways continues to represent a major objective, together with the study of potential cross-talks in these cellular events. In parallel, evaluation of the impact of countermeasures at the cellular and molecular levels in short- and long-term disuse experimentations or microgravity environments should undoubtedly and synergistically increase our basic knowledge in attempts to identify new physical, pharmacological and nutritional targets to counteract muscle atrophy. These investigations are important as skeletal muscle atrophy remains an important neuromuscular challenge with impact in clinical and social settings affecting a variety of conditions such as those seen in aging, cancer cachexia, muscle pathologies and long-term space exploration.

Figure 1

Schematic diagram of signalling pathways involved in skeletal muscle remodelling and atrophy following disuse. (A) Skeletal muscle disuse is associated with a decrease in protein synthesis involving the deactivation of the PI3K/Akt/mTOR pathway. (B) Different proteolytic systems are also involved and operate to degrade cellular proteins, but their relative contribution and importance differ significantly. (B1) Lysosomal system. (B2) Cytosolic non-lysosomal calpain system. (B3) Ubiquitin-proteasome system. The latter of which appears to catalyse the majority of protein breakdown. On the left, the Akt/FOXO transcriptional control pathway is shown leading to the induction of atrogenes (ubiquitin ligases). On the right, a specific NF-κB pathway is activated during disuse atrophy. (C) Apoptotic pathways are also shown as they represent additional events controlling muscle atrophy. (C1) and (C2) highlight apoptosis induced in a caspase-dependent versus caspase-independent manner, respectively. (D) Myostatin pathway. Myostatin, growth differentiation factor-8 (GDF8), a member of the TGF-β, is a negative regulator of muscle mass acting via Smad transcription factors. See text in first section for details.