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 re...

Full description

Saved in:
Bibliographic Details
Published in:Life science alliance 2024-11, Vol.7 (11), p.e202402885
Main Authors: Shrager, Joseph B, Randle, Ryan, Lee, Myung, Ahmed, Syed Saadan, Trope, Winston, Lui, Natalie, Poultsides, George, Liou, Doug, Visser, Brendan, Norton, Jeffrey A, Nesbit, Shannon M, He, Hao, Kapula, Ntemena, Wallen, Bailey, Fatodu, Emmanuel, Sadeghi, Cheyenne A, Konsker, Harrison B, Elliott, Irmina, Guenthart, Brandon, Backhus, Leah, Cooke, Roger, Berry, Mark, Tang, Huibin
Format: Article
Language:English
Subjects:
Adult
Female
Humans
Janus Kinase Inhibitors - pharmacology
Janus Kinases - metabolism
Male
Middle Aged
Muscle Contraction - drug effects
Muscle Fibers, Skeletal - drug effects
Muscle Fibers, Skeletal - metabolism
Muscle, Skeletal - drug effects
Muscle, Skeletal - metabolism
Piperidines - pharmacology
Pyrimidines - pharmacology
Pyrroles - pharmacology
Signal Transduction - drug effects
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 ( = 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.
ISSN:2575-1077
2575-1077
DOI:10.26508/lsa.202402885