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Am J Physiol Endocrinol Metab. 2016 Sep 1;311(3):E594-604. doi: 10.1152/ajpendo.00257.2016. Epub 2016 Jul 5.

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

Author information

Royal Derby Medical School, Royal Derby Hospital, Derby, United Kingdom;
MRC-ARUK Centre for Musculoskeletal Ageing Research, ARUK Centre for Sport, Exercise, and Osteoarthritis, School of Life Sciences, The Medical School, University of Nottingham, Nottingham, United Kingdom;
Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada;
Departments of Neurobiology, Physiology and Behavior, and Physiology and Membrane Biology, University of California Davis, Veterans Affairs Northern California Health Care System, Mather, California;
Departments of Internal Mediciane and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa; Iowa City Veterans Affairs Medical Center, Iowa City, Iowa; and.
Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania.


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.


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

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