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Am J Physiol Regul Integr Comp Physiol. 2016 Apr 15;310(8):R707-10. doi: 10.1152/ajpregu.00550.2015. Epub 2016 Feb 10.

Janus kinase inhibition prevents cancer- and myocardial infarction-mediated diaphragm muscle weakness in mice.

Author information

1
Rigel Pharmaceuticals, South San Francisco, California;
2
Department of Physical Therapy, University of Florida, Gainesville, Florida; and.
3
Rigel Pharmaceuticals, South San Francisco, California; tkinsella@rigel.com.
4
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida.

Abstract

Respiratory dysfunction is prevalent in critically ill patients and can lead to adverse clinical outcomes, including respiratory failure and increased mortality. Respiratory muscles, which normally sustain respiration through inspiratory muscle contractions, become weakened during critical illness, and recent studies suggest that respiratory muscle weakness is related to systemic inflammation. Here, we investigate the pathophysiological role of the inflammatory JAK1/3 signaling pathway in diaphragm weakness in two distinct experimental models of critical illness. In the first experiment, mice received subcutaneous injections of PBS or C26 cancer cells and were fed chow formulated with or without the JAK1/3 inhibitor R548 for 26 days. Diaphragm specific force was significantly reduced in tumor-bearing mice receiving standard chow; however, treatment with the JAK1/3 inhibitor completely prevented diaphragm weakness. Diaphragm cross-sectional area was diminished by ∼25% in tumor-bearing mice but was similar to healthy mice in tumor-bearing animals treated with R548. In the second study, mice received sham surgery or coronary artery ligation, leading to myocardial infarction (MI), and were treated with R548 or vehicle 1 h postsurgery, and once daily for 3 days. Diaphragm specific force was comparable between sham surgery/vehicle, sham surgery/R548 and MI/R548 groups, but significantly decreased in the MI/vehicle group. Markers of oxidative damage and activated caspase-3, mechanisms previously identified to reduce muscle contractility, were not elevated in diaphragm extracts. These experiments implicate JAK1/3 signaling in cancer- and MI-mediated diaphragm weakness in mice, and provide a compelling case for further investigation.

KEYWORDS:

Janus kinase; critical illness; diaphragm; wasting

PMID:
26864813
PMCID:
PMC4867416
DOI:
10.1152/ajpregu.00550.2015
[Indexed for MEDLINE]
Free PMC Article

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