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

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

doi:10.1172/JCI68523

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

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

Wei A He, Emanuele Berardi, Veronica M Cardillo, Swarnali Acharyya, Paola Aulino, Jennifer Thomas-Ahner, Jingxin Wang, Mark Bloomston, Peter Muscarella, Peter Nau, …

The Journal of clinical investigation, Vol.123(11), pp.4821-4835

11/01/2013

DOI: 10.1172/JCI68523

PMCID: PMC3809785

PMID: 24084740

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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.

Details

Title: Subtitle: NF-κB–mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia
Creators: Wei A He - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Emanuele Berardi - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Veronica M Cardillo - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Swarnali Acharyya - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Paola Aulino - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Jennifer Thomas-Ahner - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Jingxin Wang - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Mark Bloomston - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Peter Muscarella - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Peter Nau - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Nilay Shah - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Matthew E.R Butchbach - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Katherine Ladner - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Sergio Adamo - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Michael A Rudnicki - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Charles Keller - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Dario Coletti - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Federica Montanaro - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Denis C Guttridge - Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.123(11), pp.4821-4835
DOI: 10.1172/JCI68523
PMID: 24084740
PMCID: PMC3809785
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 11/01/2013
Academic Unit: Surgery
Record Identifier: 9984051585902771

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