Disuse-induced muscle wasting

Abstract

Loss of skeletal muscle mass occurs frequently in clinical settings in response to joint immobilization and bed rest, and is induced by a combination of unloading and inactivity. Disuse-induced atrophy will likely affect every person in his or her lifetime, and can be debilitating especially in the elderly. Currently there are no good therapies to treat disuse-induced muscle atrophy, in part, due to a lack of understanding of the cellular and molecular mechanisms responsible for the induction and maintenance of muscle atrophy. Our current understanding of disuse atrophy comes from the investigation of a variety of models (joint immobilization, hindlimb unloading, bed rest, spinal cord injury) in both animals and humans. Under conditions of unloading, it is widely accepted that there is a decrease in protein synthesis, however, the role of protein degradation, especially in humans, is debated. This review will examine the current understanding of the molecular and cellular mechanisms regulating muscle loss under disuse conditions, discussing the similarities and areas of dispute between the animal and human literature. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: Protein degradation; Protein synthesis; Reloading; Ubiquitin ligases; Unloading.

Fig. 1

Effect of hindlimb unloading and reloading on muscle mass. Muscle wet weight of the soleus (Sol), medial gastrocnemius (MG), tibialis anterior (TA), and extensor digitorum longus (EDL) of female Sprague Dawley rats following hindlimb unloading for 21 days (A) and hindlimb unloading for 14 days followed by 14 days of reloading (B). Data points are mean ± SD (n = 10/time point). A separate cohort of controls was taken at the start (start of HLS) and end (shaded area) of the experiment to assess normal growth over the 28 day experiment. The control rats were allowed food and water ad libitum over the 28 day period.

Fig. 2

Regulation of mTORC1 activation. Schematic diagram illustrating potential signaling pathways that could contribute to the inhibition of mTORC1 (mTOR, raptor, GβL (also known as mLST8)), and contribute to muscle loss following unloading and muscle regrowth following reloading. The proteins depicted in RED are known inhibitors of mTORC1.