Maintenance of muscle mass and load-induced growth in Muscle RING Finger 1 null mice with age.
Age-related loss of muscle mass occurs to varying degrees in all individuals and has a detrimental effect on morbidity and mortality. Muscle RING Finger 1 (MuRF1), a muscle-specific E3 ubiquitin ligase, is believed to mediate muscle atrophy through the ubiquitin proteasome system (UPS). Deletion of MuRF1 (KO) in mice attenuates the loss of muscle mass following denervation, disuse, and glucocorticoid treatment; however, its role in age-related muscle loss is unknown. In this study, skeletal muscle from male wild-type (WT) and MuRF1 KO mice was studied up to the age of 24 months. Muscle mass and fiber cross-sectional area decreased significantly with age in WT, but not in KO mice. In aged WT muscle, significant decreases in proteasome activities, especially 20S and 26S β5 (20-40% decrease), were measured and were associated with significant increases in the maladaptive endoplasmic reticulum (ER) stress marker, CHOP. Conversely, in aged MuRF1 KO mice, 20S or 26S β5 proteasome activity was maintained or decreased to a lesser extent than in WT mice, and no increase in CHOP expression was measured. Examination of the growth response of older (18 months) mice to functional overload revealed that old WT mice had significantly less growth relative to young mice (1.37- vs. 1.83-fold), whereas old MuRF1 KO mice had a normal growth response (1.74- vs. 1.90-fold). These data collectively suggest that with age, MuRF1 plays an important role in the control of skeletal muscle mass and growth capacity through the regulation of cellular stress.
Departments of Neurobiology, Physiology, and Behavior, University of California Davis, Davis, CA, 95616, USA; Molecular, Cellular and Integrative Physiology Graduate Group, University of California Davis, Davis, CA, 95616, USA.
Darren T
DT
Hwee
Leslie M
LM
Baehr
Andrew
A
Philp
Keith
K
Baar
Sue C
SC
Bodine
D000375:Aging / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight; D002196:Capillaries / Q000254:growth & development; D059865:Endoplasmic Reticulum Stress; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency* / Q000378:metabolism; D009132:Muscles / Q000033:anatomy & histology* / Q000098:blood supply / Q000378:metabolism / Q000502:physiology*; D009929:Organ Size; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000378:metabolism; D016474:Weight-Bearing
D015415:Biomarkers; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
ER Stress; anabolic resistance; sarcopenia; ubiquitin proteasome system