Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence

Abstract

Muscle wasting resulting wholly or in part from disuse represents a serious medical complication that, when prolonged, can increase morbidity and mortality. Although much knowledge has been gained over the past half century, the underlying etiology by which disuse alters muscle proteostasis remains enigmatic. Multidisciplinary and novel methodologies are needed to fill gaps and overcome barriers to improved patient care. The present review highlights seminal concepts from a symposium at Experimental Biology 2016. These proceedings focus on 1) the role of insulin resistance in mediating disuse-induced changes in muscle protein synthesis (MPS) and breakdown (MPB), as well as cross-talk between carbohydrate and protein metabolism; 2) the relative importance of MPS/MPB in mediating involuntary muscle loss in humans and animals; 3) interpretative limitations associated with MPS/MPB "markers," e.g., MuRF1/MAFbx mRNA; and finally, 4) how OMIC technologies can be leveraged to identify molecular pathways (e.g., ATF4, p53, p21) mediating disuse atrophy. This perspective deals primarily with "simple atrophy" due to unloading. Nonetheless, it is likely that disuse is a pervasive contributor to muscle wasting associated with catabolic disease-related atrophy (i.e., due to associated sedentary behaviour of disease burden). Key knowledge gaps and challenges are identified to stimulate discussion and identify opportunities for translational research. Data from animal and human studies highlight both similarities and differences. Integrated preclinical and clinical research is encouraged to better understand the metabolic and molecular underpinnings and translational relevance,for disuse atrophy. These approaches are crucial to clinically prevent or reverse muscle atrophy, thereby reestablishing homeostasis and recovery.

Keywords: activating transcription factor 4; disuse atrophy; muscle ring finger 1; protein degradation; protein synthesis.

Fig. 1.

Putative mechanism underpinning the observed changes in muscle protein synthesis, muscle protein breakdown, and muscle insulin resistance in immobilization (less likely) and sepsis-induced inflammation (highly likely). mTOR, mammalian target of rapamycin; FOXO, forkhead box O; MAFbx, muscle atrophy F-box; MuRF1, muscle RING finger 1; PDK4, pyruvate dehydrognase kinase 4; PDC, pyruvate dehydrogenase complex.

Fig. 2.

Schematic representation of the known and hypothesized changes in rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB) leading to net protein accretion or net protein loss in early (10 days or less) and later (beyond 10 days) disuse. The total daily integrated protein turnover response is represented in the bar graphs showing the daily integrated fractional synthesis rates (FSR) and fractional breakdown rates (FBR) of proteins.

Fig. 3.

Summary of the relative changes in multiple variables to 3, 7, and 14 days of tail suspension (hindlimb unloading) in adult male Fisher Brown Norway rats. The %loss of muscle mass at 14 days of hindlimb unloading is given for the soleus (SOL), medial gastrocnemius (MG), and tibialis anterior (TA) muscles. The variables measured were protein synthesis (PS), 26S β5 proteasome activity (β5), cathepsin L activity (Cath L), MuRF1 mRNA (MuRF1), MAFbx mRNA (MAFbx), FOXO1 mRNA (FOXO1), and FOXO3a mRNA (FOXO3a).

Fig. 4.

Schematic illustration of a molecular signaling pathway to skeletal muscle atrophy during limb immobilization. ATF4, activating transcription factor 4.