title: TWEAK promotes exercise intolerance by decreasing skeletal muscle oxidative phosphorylation capacity.
abstract: BACKGROUND
  Proinflammatory cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 are the major regulators of skeletal muscle mass in many catabolic conditions. However, their role in muscle metabolism remains largely unknown. In the present study, we investigated the role of TWEAK on exercise capacity and skeletal muscle mitochondrial content and oxidative metabolism.
  
  
  METHODS
  We employed wild-type and TWEAK-knockout (KO) mice and primary myotube cultures and performed biochemical, bioenergetics, and morphometric assays to evaluate the effects of TWEAK on exercise tolerance and muscle mitochondrial function and angiogenesis.
  
  
  RESULTS
  TWEAK-KO mice showed improved exercise tolerance compared to wild-type mice. Electron microscopy analysis showed that the abundance of subsarcolemmal and intermyofibrillar mitochondria is significantly increased in skeletal muscle of TWEAK-KO mice compared to wild-type mice. Furthermore, age-related loss in skeletal muscle oxidative capacity was rescued in TWEAK-KO mice. Expression of a key transcriptional regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and several other molecules involved in oxidative metabolism were significantly higher in skeletal muscle of TWEAK-KO mice. Moreover, treatment of primary myotubes with soluble TWEAK inhibited the expression of PGC-1α and mitochondrial genes and decreased mitochondrial respiratory capacity. Deletion of TWEAK also improved angiogenesis and transcript levels of vascular endothelial growth factor in skeletal muscle of mice.
  
  
  CONCLUSIONS
  These results demonstrate that TWEAK decreases mitochondrial content and oxidative phosphorylation and inhibits angiogenesis in skeletal muscle. Neutralization of TWEAK is a potential approach for improving exercise capacity and oxidative metabolism in skeletal muscle.
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 South Preston Street, Louisville, KY 40202, USA. ashok.kumar@louisville.edu.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogura
authors.forename: Vivek
authors.initials: V
authors.lastname: Mishra
authors.forename: Jonghyun
authors.initials: J
authors.lastname: Shin
authors.forename: Shephali
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar