title: Janus kinase inhibition prevents cancer- and myocardial infarction-mediated diaphragm muscle weakness in mice.
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.
authors: Rigel Pharmaceuticals, South San Francisco, California;
authors: Ira J
authors: IJ
authors: Smith
authors: Department of Physical Therapy, University of Florida, Gainesville, Florida; and.
authors: Brandon
authors: B
authors: Roberts
authors: Department of Physical Therapy, University of Florida, Gainesville, Florida; and.
authors: Adam
authors: A
authors: Beharry
authors: Rigel Pharmaceuticals, South San Francisco, California;
authors: Guillermo L
authors: GL
authors: Godinez
authors: Rigel Pharmaceuticals, South San Francisco, California;
authors: Donald G
authors: DG
authors: Payan
authors: Rigel Pharmaceuticals, South San Francisco, California; tkinsella@rigel.com.
authors: Todd M
authors: TM
authors: Kinsella
authors: Department of Physical Therapy, University of Florida, Gainesville, Florida; and.
authors: Andrew R
authors: AR
authors: Judge
authors: Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida.
authors: Leonardo F
authors: LF
authors: Ferreira
mesh_terms: D000818:Animals; D002100:Cachexia / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D003110:Colonic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003964:Diaphragm / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects*; D018908:Muscle Weakness / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects; D012120:Respiration Disorders / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3
keywords: Janus kinase; critical illness; diaphragm; wasting