TY - JOUR
T1 - NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia
AU - He, Wei A.
AU - Berardi, Emanuele
AU - Cardillo, Veronica M.
AU - Acharyya, Swarnali
AU - Aulino, Paola
AU - Thomas-Ahner, Jennifer
AU - Wang, Jingxin
AU - Bloomston, Mark
AU - Muscarella, Peter
AU - Nau, Peter
AU - Shah, Nilay
AU - Butchbach, Matthew E.R.
AU - Ladner, Katherine
AU - Adamo, Sergio
AU - Rudnicki, Michael A.
AU - Keller, Charles
AU - Coletti, Dario
AU - Montanaro, Federica
AU - Guttridge, Denis C.
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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-κB-dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-κB by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.
AB - 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-κB-dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-κB by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.
UR - http://www.scopus.com/inward/record.url?scp=84887493598&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887493598&partnerID=8YFLogxK
U2 - 10.1172/JCI68523
DO - 10.1172/JCI68523
M3 - Article
AN - SCOPUS:84887493598
SN - 0021-9738
VL - 123
SP - 4821
EP - 4835
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -