NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia.

Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly ​ to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have​ predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential​ contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and​ patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting​ in activation of both satellite and nonsatellite muscle progenitor cells. These muscle progenitors committed​ to a myogenic program, but were inhibited from completing differentiation by an event linked with persistent​ expression of the self-renewing factor Pax7. Overexpression of Pax7 was sufficient to induce atrophy in normal​ muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target,​ MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers. Furthermore, Pax7​ was induced by serum factors from cachectic mice and patients, in an NF-κ B–dependent manner, both in vitro​ and in vivo. Together, these results suggest that Pax7 responds to NF-κ B by impairing the regenerative capacity​ of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.