TWEAK promotes exercise intolerance by decreasing skeletal muscle oxidative phosphorylation capacity

Area of Science:

• Muscle physiology and metabolism
• Skeletal muscle biology
• Mitochondrial function and biogenesis

Background:

• Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 are key regulators of skeletal muscle mass during catabolic conditions.
• The specific role of TWEAK in regulating skeletal muscle metabolism and exercise capacity remains largely uncharacterized.

Purpose of the Study:

• To investigate the impact of TWEAK on exercise capacity in skeletal muscle.
• To determine the effects of TWEAK on mitochondrial content and oxidative metabolism within skeletal muscle.

Main Methods:

• Utilized wild-type and TWEAK-knockout (KO) mice, alongside primary myotube cultures.
• Employed biochemical, bioenergetics, and morphometric assays to assess exercise tolerance, mitochondrial function, and angiogenesis.

Main Results:

• TWEAK-KO mice exhibited enhanced exercise tolerance and significantly increased mitochondrial abundance in skeletal muscle compared to wild-type controls.
• Age-related decline in skeletal muscle oxidative capacity was reversed in TWEAK-KO mice, with elevated expression of PGC-1α and other oxidative metabolism markers.
• TWEAK neutralization improved angiogenesis and vascular endothelial growth factor levels in skeletal muscle, while direct TWEAK treatment inhibited mitochondrial gene expression and respiratory capacity.

Conclusions:

• TWEAK actively reduces mitochondrial content, oxidative phosphorylation, and angiogenesis in skeletal muscle.
• Neutralizing TWEAK presents a promising therapeutic strategy for enhancing exercise capacity and improving skeletal muscle oxidative metabolism.