Effect of pulmonary TNF-α overexpression on mouse isolated skeletal muscle function

Zuo L, Nogueira L, Hogan MC. Effect of pulmonary TNF-alpha overexpression on mouse isolated skeletal muscle function. Am J Physiol Regul Integr Comp Physiol 301: R1025-R1031, 2011. First published June 22, 2011; doi:10.1152/ajpregu.00126.2011.-TNF-alpha is a proinflammatory cytokine that is involved in numerous pathological processes including chronic obstructive pulmonary disease (COPD). In the present study, we used a transgenic mouse model that overexpresses TNF-alpha in the lung (Tg(+)) to test the hypothesis that chronic exposure to TNF-alpha (as seen in COPD) reduces skeletal muscle force production and fatigue resistance, particularly under low P-O2 conditions. At 7-12 mo, body and muscle weight of both extensor digitorum longus (EDL) and soleus were significantly smaller in Tg(+) compared with littermate wild-type (WT) mice; however, the body-to-muscle weight ratio was not different between groups. EDL and soleus muscles were subjected to in vitro fatiguing contractile periods under high (similar to 550 Torr) and low P-O2 (similar to 40 Torr). Although all muscles were less fatigue-resistant during low P-O2 compared with high P-O2, only the soleus fatigued more rapidly in Tg(+) mice (similar to 12%) compared with WT at high P-O2. The maximal tension of EDL was equally reduced in Tg(+) mice (28-34% decrease from WT under both P-O2 conditions); but for soleus this parameter was smaller only under low P-O2 in Tg(+) mice (similar to 31% decrease from WT). The peak rate of relaxation and the peak rate of contraction were both significantly reduced in Tg(+) EDL muscles compared with WT EDL under low P-O2 conditions, but not in soleus. These results demonstrate that TNF-alpha upregulation in the lung impairs peripheral skeletal muscle function but affects fast- and slow-twitch muscles differentially at high and low P-O2.