Skeletal muscle atrophy leads to loss and dysfunction of muscle precursor cells

Emory University, Atlanta, Georgia, United States
AJP Cell Physiology (Impact Factor: 3.78). 01/2005; 287(6):C1753-62. DOI: 10.1152/ajpcell.00292.2004
Source: PubMed


Atrophy of skeletal muscle leads to decreases in myofiber size and nuclear number; however, the effects of atrophic conditions on muscle precursor cells (MPC) are largely unknown. MPC lie outside myofibers and represent the main source of additional myonuclei necessary for muscle growth and repair. In the present study, we examined the properties of MPC after hindlimb suspension (HS)-induced atrophy and subsequent recovery of the mouse hindlimb muscles. We demonstrated that the number of MPC in atrophied muscles was decreased. RT-PCR analysis of cells isolated from atrophied muscles indicated that several mRNA characteristic of the myogenic program in MPC were absent. Cells isolated from atrophied muscles failed to properly proliferate and undergo differentiation into multinucleated myotubes. Thus atrophy led to a decrease in MPC and caused dysfunction in those MPC that remained. Upon regrowth of the atrophied muscles, these deleterious effects were reversed. Our data suggest that preventing loss or dysfunction of MPC may be a new pharmacological target during muscle atrophy.

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Available from: Grace K Pavlath, Jan 25, 2016
    • "While many causes of muscle atrophy appear to associate with the initiation of the muscle regeneration program, a prevailing hypothesis in the field is that muscle regeneration is impaired in atrophying muscle. This idea originated from a number of studies that reported that the number of precursor cells decline in atrophied muscle [81] [82] [83] [84] [85]. More recent work supports this hypothesis by demonstrating that muscle atrophied by hindlimb suspension prior to cardiotoxin injury exhibited a block in regeneration that impairs any gain in muscle mass even six weeks following acute injury [86]. "
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    ABSTRACT: While changes in muscle protein synthesis and degradation have long been known to contribute to muscle wasting, a body of literature has arisen which suggests that regulation of the satellite cell and its ensuing regenerative program are impaired in atrophied muscle. Lessons learned from cancer cachexia suggest that this regulation is simply not a consequence, but a contributing factor to the wasting process. In addition to satellite cells, evidence from mouse models of cancer cachexia also suggests that non-satellite progenitor cells from the muscle microenvironment are also involved. This chapter in the series reviews the evidence of dysfunctional muscle repair in multiple wasting conditions. Potential mechanisms for this dysfunctional regeneration are discussed, particularly in the context of cancer cachexia.
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    • ", 2010 ) . Alterations in SC function , including defective fusion properties , have also been observed in the hind limb suspension model of disuse atrophy ( Mitchell and Pavlath , 2004 ) . Conversely , changes in SC numbers are not a consistent finding in disuse atrophy , reflecting the complexity of events occurring in this context ( Brooks and Myburgh , 2014 ) . "
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    ABSTRACT: Skeletal muscle atrophy or wasting accompanies various chronic illnesses and the aging process, thereby reducing muscle function. One of the most important components contributing to effective muscle repair in postnatal organisms, the satellite cells (SCs), have recently become the focus of several studies examining factors participating in the atrophic process. We critically examine here the experimental evidence linking SC function with muscle loss in connection with various diseases as well as aging, and in the subsequent recovery process. Several recent reports have investigated the changes in SCs in terms of their differentiation and proliferative capacity in response to various atrophic stimuli. In this regard, we review the molecular changes within SCs that contribute to their dysfunctional status in atrophy, with the intention of shedding light on novel potential pharmacological targets to counteract the loss of muscle mass.
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    • "In a seminal set of experiments, Mitchell and Pavlath examined the properties of muscle precursor cells (MPCs include both SCs and other stem-like cells between myofibers, fat and in blood vessels ) after 14 days of HS in mice (Mitchell and Pavlath, 2004) and subsequent recovery. HS led to decreased number of MPCs and these MPCs taken from atrophied muscle cells could not proliferate and differentiate in vitro into normal myonucleated myotubes. "
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    ABSTRACT: Maintenance of skeletal muscle is essential for health and survival. There are marked losses of skeletal muscle mass as well as strength and physiological function under conditions of low mechanical load, such as space flight, as well as ground based models such as bed rest, immobilization, disuse, and various animal models. Disuse atrophy is caused by mechanical unloading of muscle and this leads to reduced muscle mass without fiber attrition. Skeletal muscle stem cells (satellite cells) and myonuclei are integrally involved in skeletal muscle responses to environmental changes that induce atrophy. Myonuclear domain size is influenced differently in fast and slow twitch muscle, but also by different models of muscle wasting, a factor that is not yet understood. Although the myonuclear domain is 3-dimensional this is rarely considered. Apoptosis as a mechanism for myonuclear loss with atrophy is controversial, whereas cell death of satellite cells has not been considered. Molecular signals such as myostatin/SMAD pathway, MAFbx, and MuRF1 E3 ligases of the ubiquitin proteasome pathway and IGF1-AKT-mTOR pathway are 3 distinctly different contributors to skeletal muscle protein adaptation to disuse. Molecular signaling pathways activated in muscle fibers by disuse are rarely considered within satellite cells themselves despite similar exposure to unloading or low mechanical load. These molecular pathways interact with each other during atrophy and also when various interventions are applied that could alleviate atrophy. Re-applying mechanical load is an obvious method to restore muscle mass, however how nutrient supplementation (e.g., amino acids) may further enhance recovery (or reduce atrophy despite unloading or ageing) is currently of great interest. Satellite cells are particularly responsive to myostatin and to growth factors. Recently, the hibernating squirrel has been identified as an innovative model to study resistance to atrophy.
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