2. Academic Validation
  3. JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle

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

  • Life Sci Alliance. 2024 Aug 9;7(11):e202402885. doi: 10.26508/lsa.202402885.
Joseph B Shrager 1 2,  Ryan Randle 3 2,  Myung Lee 3 2,  Syed Saadan Ahmed 3 2,  Winston Trope 3,  Natalie Lui 3,  George Poultsides 4,  Doug Liou 3,  Brendan Visser 4,  Jeffrey A Norton 4,  Shannon M Nesbit 3,  Hao He 3,  Ntemena Kapula 3,  Bailey Wallen 3,  Emmanuel Fatodu 3 2,  Cheyenne A Sadeghi 3,  Harrison B Konsker 3 2,  Irmina Elliott 3 2,  Brandon Guenthart 3,  Leah Backhus 3 2,  Roger Cooke 5,  Mark Berry 3,  Huibin Tang 6 2
Affiliations

Affiliations

  • 1 https://ror.org/00f54p054 Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA shrager@stanford.edu.
  • 2 VA Palo Alto Healthcare System, Palo Alto, CA, USA.
  • 3 https://ror.org/00f54p054 Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 https://ror.org/00f54p054 Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Department of Biochemistry, University of California, San Francisco, CA, USA.
  • 6 https://ror.org/00f54p054 Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA tanghb@stanford.edu.
PMID: 39122555 DOI: 10.26508/lsa.202402885
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.

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