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: 5.94). 08/2013; DOI: 10.1111/acel.12150
Source: PubMed

ABSTRACT 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.


Available from: Keith Baar, May 24, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This review provides an overview of the adaptive changes in several regulators of muscle mass in both sarcopenia and muscular dystrophy.
    Frontiers in Aging Neuroscience 08/2014; 6:230. DOI:10.3389/fnagi.2014.00230 · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: extracellular matrix (ECM) components are instrumental in maintaining homeostasis and muscle fiber functional integrity. Skeletal muscle hypertrophy is associated with ECM remodeling. Specifically, recent studies have reported the involvement of matrix metalloproteinases (MMPs) in muscle ECM remodeling. However, the functional role of MMPs in muscle hypertrophy remains largely unknown. in this study, we examined the role of MMP-2 in skeletal muscle hypertrophy using a previously validated method where the plantaris muscle of mice were subjected to mechanical overload due to the surgical removal of synergist muscles (gastrocnemius and soleus). following two weeks of overload, we observed a significant increase in MMP-2 activity and up-regulation of ECM components and remodeling enzymes in the plantaris muscles of wild-type mice. However, MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to their wild-type littermates. Investigation of protein synthesis rate and Akt/mTOR signaling revealed no difference between wild-type and MMP-2 knockout mice, suggesting that a difference in hypertrophy was independent of protein synthesis. taken together, our results suggest that MMP-2 is a key mediator of ECM remodeling in the setting of skeletal muscle hypertrophy.
  • [Show abstract] [Hide abstract]
    ABSTRACT: In a mature (weight neutral) animal, an increase in muscle mass only occurs when the muscle is loaded sufficiently to cause an increase in myofibrillar protein balance. A tight relationship between muscle hypertrophy, acute increases in protein balance, and the activity of the mechanistic target of rapamycin complex 1 (mTORC1) was demonstrated 15 years ago. Since then, our understanding of the signals that regulate load-induced hypertrophy has evolved considerably. For example, we now know that mechanical load activates mTORC1 in the same way as growth factors, by moving TSC2 (a primary inhibitor of mTORC1) away from its target (the mTORC activator) Rheb. However, the kinase that phosphorylates and moves TSC2 is different in the two processes. Similarly, we have learned that a distinct pathway exists whereby amino acids activate mTORC1 by moving it to Rheb. While mTORC1 remains at the forefront of load-induced hypertrophy, the importance of other pathways that regulate muscle mass are becoming clearer. Myostatin, is best known for its control of developmental muscle size. However, new mechanisms to explain how loading regulates this process are suggesting that it could play an important role in hypertrophic muscle growth as well. Last, new mechanisms are highlighted for how β2 receptor agonists could be involved in load-induced muscle growth and why these agents are being developed as non-exercise-based therapies for muscle atrophy. Overall, the results highlight how studying the mechanism of load-induced skeletal muscle mass is leading the development of pharmaceutical interventions to promote muscle growth in those unwilling or unable to perform resistance exercise.
    Calcified Tissue International 10/2014; 96(3). DOI:10.1007/s00223-014-9925-9 · 2.75 Impact Factor