Respiratory and limb muscle weakness induced by tumor necrosis factor-alpha: involvement of muscle myofilaments

Am J Respir Crit Care Med. 2002 Aug 15;166(4):479-84. doi: 10.1164/rccm.2202005.


The respiratory and limb skeletal muscles become weakened in sepsis, congestive heart failure, and other inflammatory diseases. A potential mediator of muscle weakness is tumor necrosis factor (TNF)-alpha, a cytokine that can stimulate muscle wasting and also can induce contractile dysfunction without overt catabolism. This study addressed the latter process. Murine diaphragm and limb muscle (flexor digitorum brevis [FDB]) preparations were used to determine the relative sensitivities of these muscles to TNF-alpha. Intact muscle fibers were isolated from FDB and microinjected with indo-1 to measure changes in sarcoplasmic calcium regulation. We found that TNF-alpha depressed tetanic force of the diaphragm and FDB to comparable degrees across a range of stimulus frequencies. In isolated muscle fibers, TNF-alpha decreased tetanic force without altering tetanic calcium transients or resting calcium levels. We conclude that (1) TNF-alpha compromises contractile function of diaphragm and limb muscle similarly, and (2) TNF-alpha decreases force by blunting the response of muscle myofilaments to calcium activation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin Cytoskeleton / physiology
  • Animals
  • Calcium / analysis
  • Calcium / physiology
  • Chronic Disease
  • Disease Models, Animal*
  • Disease Progression
  • Heart Diseases / complications
  • Homeostasis
  • In Vitro Techniques
  • Inflammation
  • Isometric Contraction / physiology*
  • Lung Diseases / complications
  • Male
  • Mice
  • Mice, Inbred Strains
  • Muscle Weakness / etiology*
  • Muscle Weakness / pathology
  • Muscle Weakness / physiopathology*
  • Respiratory Paralysis / etiology*
  • Respiratory Paralysis / pathology
  • Respiratory Paralysis / physiopathology*
  • Tumor Necrosis Factor-alpha / physiology*


  • Tumor Necrosis Factor-alpha
  • Calcium