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

Area of Science:

• Muscle physiology
• Pharmacology
• Immunology

Background:

• Muscle contractile force reduction is linked to significant morbidity and mortality.
• The JAK-STAT pathway is a key signaling pathway implicated in various cellular processes.

Purpose of the Study:

• To investigate the effect of Janus kinase (JAK) inhibition on contractile force in normal human skeletal muscle.
• To explore the underlying molecular mechanisms of JAK inhibition's impact on muscle function.

Main Methods:

• Human muscle biopsies were obtained from participants randomized to receive tofacitinib or placebo for 48 hours.
• Single-fiber contractile force measurements were performed on diaphragm and serratus anterior myofibers.
• Molecular analyses included assessment of protein oxidation, FoxO-ubiquitination-proteasome signaling, and myosin light chain kinase (MYLK) levels.

Main Results:

• Tofacitinib treatment significantly increased the maximum specific force of diaphragm and serratus anterior muscle fibers by 15.7% compared to placebo.
• The enhanced contractile force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling.
• Increased levels of smooth muscle myosin light chain kinase (MYLK) were observed, and MYLK inhibition attenuated the tofacitinib-induced force increase.

Conclusions:

• JAK inhibition, specifically with tofacitinib, enhances skeletal muscle contractile force in humans.
• The observed effects are mediated by reduced protein oxidation, altered proteasome signaling, and modulation of MYLK.
• Inhibition of the JAK-STAT pathway presents a potential therapeutic strategy for clinical conditions characterized by muscle dysfunction.