Chronic p53 activity leads to skeletal muscle atrophy and muscle stem cell perturbation

p53 tumor suppressor activity has been proposed to regulate the rate of ageing in part by suppressing postnatal stem cell numbers. Severe and rapid skeletal muscle atrophy is a hallmark of cachexia whereas muscle atrophy that occurs during aging (sarcopenia) has a slower rate of progression. Despite these differences, these two forms of muscle atrophy share many features although it remains unclear whether these processes are regulated by the same key regulatory factors. We demonstrated a requirement for p53 function in mediating severe and rapid cachexia induced by tumor load. Furthermore, the p53 target gene, PW1, activates p53 providing a potential positive feedback loop whereby a stress response is amplified in muscle cells. In the presence of TNF, a p53/PW1-dependent pathway mediates the block of myogenic differentiation in vitro and in vivo. To further characterize how p53 and PW1 mediate muscle atrophy, we analyzed a mouse model in which chronic p53 hyperactivation leads to early onset aging. We demonstrate that p53 hyperactivity is sufficient to induce muscle atrophy consistent with sarcopenia in ageing muscle. We observe that this process is accompanied by alterations in the distribution, but not in the number of muscle stem cells. Finally, we demonstrate that p53 upregulates PW1 expression in muscle in vitro and in vivo. Taken together, our data demonstrate that p53 and PW1 activities are required in promoting muscle atrophy induced by cytokines.