Wasting Away
Skeletal muscle wasting (cachexia) is a debilitating condition seen in patients with a variety of diseases including cancer. Most research on the underlying mechanisms of cachexia progression has focused on developed muscle fibers. Wei He and colleagues at Ohio State University found an association between cachexia and activation of satellite and non-satellite muscle progenitor cells in tumor-bearing mice and pancreatic cancer patients. These muscle precursor cells began myogeneisis, but were unable to complete differentiation. This arrested development was associated with inappropriate expression of the self-renewal factor Pax7. Decreasing either Pax7 or increasing expression of MyoD, which Pax7 inhibits, restored muscle cell differentiation and increased muscle mass in tumor-bearing mice. Furthermore, dysregulation of Pax7 was induced in an NF-κB-dependent manner. This study suggests that therapies targeting Pax7 may alleviate muscle wasting in cancer patients. The above immunofluorescent image shows the location of Pax7+ muscle progenitor cells (red) and muscle fiber size (green outline) in normal tissue (left). Induction of NF-κB in Pax7+ cells (as indicated by loss of red signal) results in reduced muscle fiber size (green outline) and increased Pax7 expression (not shown). DAPI (blue) staining is also shown.
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Abstract
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.
Authors
Wei A. He, Emanuele Berardi, Veronica M. Cardillo, Swarnali Acharyya, Paola Aulino, Jennifer Thomas-Ahner, Jingxin Wang, Mark Bloomston, Peter Muscarella, Peter Nau, Nilay Shah, Matthew E.R. Butchbach, Katherine Ladner, Sergio Adamo, Michael A. Rudnicki, Charles Keller, Dario Coletti, Federica Montanaro, Denis C. Guttridge
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ISSN: 0021-9738 (print), 1558-8238 (online)