Maintenance of Muscle Mass and Load-Induced Growth in Muscle RING Finger 1 Null Mice with Age.

Departments of Neurobiology, Physiology, and Behavior, University of California, Davis, CA, 95616
Aging cell (Impact Factor: 6.34). 08/2013; 13(1). DOI: 10.1111/acel.12150
Source: PubMed


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 were studied up to the age of 24 months. Muscle mass and fiber cross-sectional area decreased significantly with age in WT, but not 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 following functional overload, revealed that WT mice had significantly less growth relative to young mice (1.37 vs. 1.83 fold), whereas 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. This article is protected by copyright. All rights reserved.

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    • "Interestingly, recent findings indicate that atrogin-1-knockout mice are short-lived and experience higher loss of muscle mass during aging than control mice (Sandri et al., 2013), indicating that the activity of this E3 ubiquitin ligase is required to preserve muscle mass during aging in mice. Moreover, MuRF-1-null mice experience higher decay of muscle strength during aging than controls, although muscle mass is at least in part preserved in these mice (Hwee et al., 2014). As indicated by Sandri et al. (2013), chronic inhibition of these atrogenes should not be considered a therapeutic target to counteract sarcopenia because this does not prevent muscle loss but instead exacerbates weakness. "
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    • "Fourteen days of overload produced significant growth of the plantaris in both female and male MuRF1 KO mice, which was similar to that observed in WT mice of both genders (Figure 5). This result is comparable to what has been previously reported for male MuRF1 KO mice (Hwee et al., 2013). In contrast, the deletion of MAFbx appeared to have a significant effect on loadinduced growth, especially in female mice (Figure 5). "
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