Hampered muscle homeostasis and functional recovery in the presence of cytokines

Cachexia, a debilitating muscle wasting syndrome, increases mortality and morbidity of a significant fraction of chronically hill as well as ICU patients. We use tumor (C26)-bearing mice and TNF expressing mice as models of cachexia. In the presence of elevated levels of cytokines several populations of cells with myogenic potential are stable or increased in muscle, including satellite (Pax7-expressing) cells, hematopoietic stem (Sca1- CD45-expressing) cells and muscle interstitial stem (Sca1- CD34-expressing) cells also characterized by PW1expression. PW1 is involved in myogenic cell differentiation, fiber size control and p53-mediated pathways. The increase in myogenic cells in cachectic muscle suggests an attempt to cope with wasting by activation of a myogenic response. Nonetheless, we observe that muscle regenerative capacity is reduced by cytokines. TNF negatively affects the onset of regenerating fibers, without exacerbating fiber death following focal injury. Several interstitial cells, expressing Sca1, CD34 and PW1, show caspase activity during regeneration and the number of caspase activated cells is markedly increased by TNF, concomitant with an inhibition in regeneration. Block of caspase activity improves muscle regeneration either in the absence or presence of TNF. Muscle treatment with the myogenic factor vasopressin (AVP) counteracts TNF effects on regeneration. Regeneration extent affects muscle performance and AVP-mediated rescue of TNF effects results in functional recovery of the regenerated muscle similar to controls. Our data show that cytokine negative effects on muscle are counteracted by hormonal or pharmacological approaches. They also highlight the importance of proper muscle regeneration for functional recovery of muscle tissue.