Abstract
Muscle homeostasis involves de novo myogenesis, as observed in conditions of acute or chronic muscle damage. Tumor Necrosis Factor (TNF) triggers skeletal muscle wasting in several pathological conditions and inhibits muscle regeneration. We show that intramuscular treatment with the myogenic factor Arg8-vasopressin (AVP) enhanced skeletal muscle regeneration and rescued the inhibitory effects of TNF on muscle regeneration. The functional analysis of regenerating muscle performance following TNF or AVP treatments revealed that these factors exerted opposite effects on muscle function. Principal component analysis showed that TNF and AVP mainly affect muscle tetanic force and fatigue. Importantly, AVP counteracted the effects of TNF on muscle function when delivered in combination with the latter. Muscle regeneration is, at least in part, regulated by caspase activation, and AVP abrogated TNF-dependent caspase activation. The contrasting effects of AVP and TNF in vivo are recapitulated in myogenic cell cultures, which express both PW1, a caspase activator, and Hsp70, a caspase inhibitor. We identified PW1 as a potential Hsp70 partner by screening for proteins interacting with PW1. Hsp70 and PW1 co-immunoprecipitated and co-localized in muscle cells. In vivo Hsp70 protein level was upregulated by AVP, and Hsp70 overexpression counteracted the TNF block of muscle regeneration. Our results show that AVP counteracts the effects of TNF through cross-talk at the Hsp70 level. Therefore, muscle regeneration, both in the absence and in the presence of cytokines may be enhanced by increasing Hsp70 expression.
Highlights
The maintenance of regenerative capacity through recruitment or activation of resident stem cells is important for skeletal muscle recovery following injury or disuse [1,2,3]
In order to test the ability of AVP to counteract Tumor Necrosis Factor (TNF)-mediated inhibition of muscle differentiation, we induced differentiation of the myogenic cell line L6 in the absence or in the presence of TNF, AVP, or TNF and AVP combined
Chronic exposure to inflammatory cytokines is deleterious for skeletal muscle homeostasis and function in a variety of pathological conditions [4,36]
Summary
The maintenance of regenerative capacity through recruitment or activation of resident stem cells is important for skeletal muscle recovery following injury or disuse [1,2,3]. Tumor necrosis factor-a ( referred to as TNF, in agreement with Clark [7]) is a principal cytokine involved in the pathogenesis of muscular dystrophy and other disease states such as cachexia [8,9,10]. Prolonged exposure to TNF is known to block myogenic cell differentiation and muscle regeneration [6,11]. This occurs, at least in part, through non-apoptotic caspase activation in myogenic cells in vitro, which is observed in interstitial stem cells in the regenerating muscle following focal injury [6]. PW1 is responsible for the recruitment of caspase-dependent pathways that inhibit muscle differentiation in vitro as well as muscle regeneration [6,11,12,15]
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