p66ShcA and oxidative stress modulate myogenic differentiation and skeletal muscle regeneration after hind limb ischemia

Oxidative stress plays a pivotal role in ischemic injury, and p66ShcAko mice exhibit both lower oxidative stress and decreased tissue damage following hind limb ischemia. Thus, it was investigated whether tissue regeneration following acute hind limb ischemia was altered in p66ShcAko mice. Upon femoral artery dissection, muscle regeneration started earlier and was completed faster than in wild-type (WT) control. Moreover, faster regeneration was associated with decreased oxidative stress. Unlike ischemia, cardiotoxin injury induced similar skeletal muscle damage in both genotypes. However, p66ShcAko mice regenerated faster, in agreement with the regenerative advantage upon ischemia. Since no difference between p66ShcAwt and knock-out (ko) mice was found in blood perfusion recovery after ischemia, satellite cells (SCs), a resident population of myogenic progenitors, were examined. Similar SCs numbers were present in WT and ko mice. However, in vitro cultured p66ShcAko SCs displayed lower oxidative stress levels and higher proliferation rate and differentiated faster than WT. Furthermore, when exposed to sublethal H2O2 doses, p66ShcAko SCs were resistant to H2O2- induced inhibition of differentiation. Finally, myogenic conversion induced by MyoD overexpression was more efficient in p66ShcAko fibroblasts compared with WT. The present work demonstrates that oxidative stress and p66ShcA play a crucial role in the regenerative pathways activated by acute ischemia.