Cytokines alter number and function of cell populations relevant to skeletal muscle homeostasis

The maintenance of a working skeletal musculature is conferred by its remarkable ability to regenerate after mechanical or pathological injury. However muscle atrophies are characterized by the progressive loss of muscle tissue due to alterations of skeletal muscle homeostasis. In particular cachexia is a severe syndrome consisting of marked skeletal muscle atrophy, characterized by a dramatic loss of muscle mass associated with a compromised regenerative ability. Arg-vasopressin (AVP) is a potent myogenesis promoting factor and activates both the calcineurin and CaMK pathways, whose combined activation leads to the formation of transcription factor complexes in vitro (2, 3). The local over-expression of the V1a AVP receptor (V1aR) in injured muscle results in enhanced regeneration. V1aR over-expressing muscle exhibits: early activation of satellite cells and regeneration markers, accelerated differentiation, increased cell population expressing hematopoietic stem cell markers and its conversion to the myogenic lineage. Here we investigate the role of V1aR overexpression in animals undergoing cachexia as a result of muscle over-expression of a specific cytokine (TNF) (1). In these conditions, the local V1aR over-expression counteracts the negative effects of TNF on muscle, as demonstrated by morphological and biochemical analysis. In particular, the presence of V1aR results in increased Pax-7, myogenin and myosin expression levels both in control and in cachectic muscles. We demonstrate that V1aR over-expressing muscle increases calcineurin and IL-4 expression levels, and induces the phosphorylation of FOXO trascription factors, inhibiting the expression of atrophic genes.This study highlights a novel in vivo role for the AVP-dependent pathways which may represent a potential gene therapy approach for many diseases affecting muscle homeostasis.