Muscle sparing in muscle RING finger 1 null mice: response to synthetic glucocorticoids

• Published in: The Journal of physiology Vol. 589; no. 19; pp. 4759 - 4776
• Main Authors: Baehr, Leslie M., Furlow, J. David, Bodine, Sue C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2011; Wiley Subscription Services, Inc; Blackwell Science Inc
• Subjects: Animals; Dexamethasone - pharmacology; Female; Forkhead Transcription Factors - genetics; Glucocorticoids - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction - drug effects; Muscle Contraction - genetics; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - chemically induced; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Musculoskeletal system; Proteasome Endopeptidase Complex - metabolism; Protein Biosynthesis - drug effects; Protein synthesis; Proteins; Proteolysis - drug effects; RING Finger Domains - genetics; Rodents; Skeletal Muscle and Exercise; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Tripartite Motif Proteins; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.212845

Non‐Technical Summary  Skeletal muscle has the capacity to modify its size in response to external cues such as mechanical load, neural activity, hormones, stress and nutritional status. Pathological muscle loss or ‘atrophy’ occurs as the result of a number of disparate conditions including ageing, immobilization, diabetes, cancer, sepsis and as a serious side effect of corticosteroid hormone treatment. Synthetic glucocorticoids are often used to treat inflammation; however, high doses and chronic use of these hormones can lead to the loss of skeletal muscle mass and weakness. We show that in mice with a deletion of the MuRF1 protein, but not the MAFbx protein, the loss of muscle mass is attenuated relative to normal mice following 14 days of glucocorticoid treatment. Knowledge of how the MuRF1 protein functions in skeletal muscle to regulate skeletal muscle mass could lead to the development of therapeutics to prevent muscle atrophy under various conditions including glucocorticoid treatment.
  Skeletal muscle atrophy occurs under a variety of conditions and can result from alterations in both protein synthesis and protein degradation. The muscle‐specific E3 ubiquitin ligases, MuRF1 and MAFbx, are excellent markers of muscle atrophy and increase under divergent atrophy‐inducing conditions such as denervation and glucocorticoid treatment. While deletion of MuRF1 or MAFbx has been reported to spare muscle mass following 14 days of denervation, their role in other atrophy‐inducing conditions is unclear. The goal of this study was to determine whether deletion of MuRF1 or MAFbx attenuates muscle atrophy after 2 weeks of treatment with the synthetic glucocorticoid dexamethasone (DEX). The response of the triceps surae (TS) and tibialis anterior (TA) muscles to 14 days of DEX treatment (3 mg kg−1 day−1) was examined in 4 month‐old male and female wild type (WT) and MuRF1 or MAFbx knock out (KO) mice. Following 14 days of DEX treatment, muscle wet weight was significantly decreased in the TS and TA of WT mice. Comparison of WT and KO mice following DEX treatment revealed significant sparing of mass in both sexes of the MuRF1 KO mice, but no muscle sparing in MAFbx KO mice. Further analysis of the MuRF1 KO mice showed significant sparing of fibre cross‐sectional area and tension output in the gastrocnemius (GA) after DEX treatment. Muscle sparing in the MuRF1 KO mice was related to maintenance of protein synthesis, with no observed increases in protein degradation in either WT or MuRF1 KO mice. These results demonstrate that MuRF1 and MAFbx do not function similarly under all atrophy models, and that the primary role of MuRF1 may extend beyond controlling protein degradation via the ubiquitin proteasome system.