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Dev Cell. 2018 Jun 18;45(6):712-725.e6. doi: 10.1016/j.devcel.2018.05.026.

Twist1 Activation in Muscle Progenitor Cells Causes Muscle Loss Akin to Cancer Cachexia.

Author information

1
Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA.
2
Endocrinology, Diabetology, and Nutrition Department, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
3
Department of Applied Oral Sciences, The Forsyth Institute, Harvard School of Dental Medicine Affiliate, Cambridge, MA 02142, USA.
4
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris 75012, France.
5
Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA; Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris 75012, France. Electronic address: aatfi@umc.edu.

Abstract

Cancer cachexia is characterized by extreme skeletal muscle loss that results in high morbidity and mortality. The incidence of cachexia varies among tumor types, being lowest in sarcomas, whereas 90% of pancreatic ductal adenocarcinoma (PDAC) patients experience severe weight loss. How these tumors trigger muscle depletion is still unfolding. Serendipitously, we found that overexpression of Twist1 in mouse muscle progenitor cells, either constitutively during development or inducibly in adult animals, caused severe muscle atrophy with features reminiscent of cachexia. Using several genetic mouse models of PDAC, we detected a marked increase in Twist1 expression in muscle undergoing cachexia. In cancer patients, elevated levels of Twist1 are associated with greater degrees of muscle wasting. Finally, both genetic and pharmacological inactivation of Twist1 in muscle progenitor cells afforded substantial protection against cancer-mediated cachexia, which translated into meaningful survival benefits, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients.

KEYWORDS:

Activin/Myostatin cytokines; Smad signaling; Twist1; cancer cachexia; muscle cachexia; muscle progenitor cells; muscle protein breakdown; pancreatic ductal adenocarcinoma

PMID:
29920276
PMCID:
PMC6054474
[Available on 2019-06-18]
DOI:
10.1016/j.devcel.2018.05.026
[Indexed for MEDLINE]

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