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

Abstract

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.

ChronicPseudomonas aeruginosaInfection and Respiratory Muscle Impairment in Cystic Fibrosis

“…33 Induced chronic bronchopulmonary infection by P. aeruginosa significantly decreased diaphragm and limb strength in infected mice, 28 and tumor necrosis factor alpha depressed the diaphragmatic tetanic force in murine diaphragm and limb muscle preparations. 8 Furthermore, in mice, endotoxin caused diaphragm weakness and contractile dysfunction. 34 Respiratory muscle function is compromised in CF, according to some studies, which reported decreased maximal respiratory pressures in hyperinflated, malnourished CF patients with airway obstruction.…”

“…5 Sex differences relating to the natural history of P. aeruginosa infection have been described in the literature: women suffer higher rates of colonization and younger age of conversion to the more aggressive mucoid phenotype, compared to men. 6,7 Chronic infection has been linked to compromised diaphragm function in animal models 8 and human patients. 9 Respiratory failure in CF is caused by parenchyma destruction, recurrent infection, and bronchiectasis, and respiratory muscle dysfunction might also play a critical role.…”

Skeletal Muscle Dysfunction in Patients with Chronic Obstructive Pulmonary Disease

“…TNFα might also reduce skeletal muscle oxidative capacity by inhibiting mitochondrial biogenesis (Valerio et al 2006). Finally, TNFα exerts acute inhibitory effects on muscle contractility (Wilcox et al 1996), which has been attributed to depressed sensitivity of myofi lament proteins to Ca ++ and to enhanced generation of ROS and RNS (Reid et al 2002). It should be emphasized that despite convincing documentation of elevated circulating levels of pro-infl ammatory cytokines in stable COPD patients, as well as in those suffering from acute exacerbations, general agreement is lacking about the degree to which pro-infl ammatory mediators are upregulated in limb muscles.…”

Association of Childhood Asthma and Pediatric Obstructive Sleep Apnea: A Retrospective Cohort Study from a Nationwide Population-based Database

“…First, the systemic inflammation may affect the strength or force generation of respiratory muscles, including the upper airway dilator muscles, and then destabilize the central breathing controller [20]. Second, the deformable pharyngeal airway duration inspiration and the active contraction of respiratory muscles during forced exhalation in an asthma attack could promote the collapse of the upper airway at night [21].…”