Respiratory and Limb Muscle Weakness Induced by Tumor Necrosis Factor- α : 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.