JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle

Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (<i>P</i> = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

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Publication Details

Journal
Life Science Alliance
Published
2024-08-09
DOI
https://doi.org/10.26508/lsa.202402885
Citations
1
Primary Topic
Exercise and Physiological Responses
Type
article
Field-Weighted Citation Impact
0.25

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article

JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle

D. Liou, Ntemena Kapula, Roger Cooke, Mark Berry et al.
1 citations
Life Science Alliance
Exercise and Physiological Responses
0.25
article

JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle

D. Liou, Ntemena Kapula, Roger Cooke, Mark Berry, Emmanuel Fatodu, Winston Trope, Shannon Nesbit, Jeffrey A. Norton, Ryan J. Randle, Myung Lee, Cheyenne Sadeghi, George A. Poultsides, Brandon A. Guenthart, Harrison B. Konsker, Irmina A. Elliott, Brendan C. Visser, Leah M. Backhus, Natalie S. Lui, Syed Saadan Ahmed, Joseph B. Shrager, Hao He, Huibin Tang, Bailey Wallen
article en
1 citations

Abstract

Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (<i>P</i> = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

Life Science AllianceVol. 7(11)
University of California, San Francisco (US), VA Palo Alto Health Care System (US), Stanford Medicine (US), Stanford University (US)
National Institutes of Health, National Heart, Lung, and Blood Institute
Good health and well-being
Openalex Percentile: Top 40%
Exercise and Physiological Responses
0.25
DOIOpen Access PDFOpenAlex
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