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

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 (P = 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.

SUBMITTER: Shrager JB

PROVIDER: S-EPMC11316201 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature

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

Shrager Joseph B JB Randle Ryan R Lee Myung M Ahmed Syed Saadan SS Trope Winston W Lui Natalie N Poultsides George G Liou Doug D Visser Brendan B Norton Jeffrey A JA Nesbit Shannon M SM He Hao H Kapula Ntemena N Wallen Bailey B Fatodu Emmanuel E Sadeghi Cheyenne A CA Konsker Harrison B HB Elliott Irmina I Guenthart Brandon B Backhus Leah L Cooke Roger R Berry Mark M Tang Huibin H

Life science alliance 20240809 11

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 ...[more]

PMID: 39122555

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

Publications

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

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