Respiratory and limb muscle weakness induced by tumor necrosis factor-alpha: involvement of muscle myofilaments.
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.
Pulmonary Medicine, Suite 520B, Baylor College of Medicine, Houston, TX 77030, USA. reid@bcm.tmc.edu
Michael B
MB
Reid
Jan
J
Lännergren
Håkan
H
Westerblad
D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D006331:Heart Diseases / Q000150:complications; D006706:Homeostasis; D066298:In Vitro Techniques; D007249:Inflammation; D007537:Isometric Contraction / Q000502:physiology*; D008171:Lung Diseases / Q000150:complications; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018908:Muscle Weakness / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D012133:Respiratory Paralysis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D002118:Calcium
Non-programmatic