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NF-κB–mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia
Wei A. He, … , Federica Montanaro, Denis C. Guttridge
Wei A. He, … , Federica Montanaro, Denis C. Guttridge
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(11):4821-4835. https://doi.org/10.1172/JCI68523.
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Research Article Oncology

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

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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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Figure 9

Pax7 deregulation and muscle wasting in cancer cachexia is dependent on NF-κB.

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Pax7 deregulation and muscle wasting in cancer cachexia is dependent on ...
(A) GAST mass from tumor-bearing control Rosa26-IKKβ (n = 15) or Pax7-CreER;Rosa26-IKKβ (n = 20) mice injected with tamoxifen. (B) Western blot for Pax7 from muscles in A. (C) Tomato+ cells from Rosa26-IKKβ and Pax7-CreER;Rosa26-IKKβ muscles probed for α-laminin and DAPI (blue). Higher-magnification views are shown below. (D) Quantitation of Tomato+ cells from C. At least 15 sections and 9 × 105 fibers from 5 mice were counted for each group. (E) GAST mass from tumor-bearing control IKKβf/f (n = 12) or Pax7-CreER;IKKβf/f (n = 18) mice injected with tamoxifen. (F) Western blot of Pax7 from muscles in E. (G) Tomato+ cells from IKKβf/f and Pax7-CreER;IKKβf/f muscle sections immunostained with α-laminin and DAPI (blue). Higher-magnification views are shown below. (H) Quantitation of Tomato+ fibers from G. At least 15 sections and 9 × 105 fibers from 3 mice were counted for each group. Scale bars: 0.5 mm (C and G, top); 100 μm (C and G, bottom). *P < 0.05, **P < 0.01.

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