Overexpression of TNF-α Reduces Skeletal Muscle Function in Mice under Low PO2 Condition

Abstract

PURPOSE: Tumor necrosis factor-α (TNF-α) is an important proinflammatory cytokine that has been involved in numerous pathological processes including chronic obstructive pulmonary disease (COPD). In the present study, TNF-α was overexpressed in alveolar type II cells in adult C57 male mice. The purpose of this study was to determine whether overexpression of TNF-α [TNF-α (+)] reduces skeletal muscle function during tetanic contractions inducing fatigue, particularly during low PO2 conditions. METHODS: Both extensor digitorum longus (EDL, fast type muscle) and soleus (slow type muscle) were carefully removed from the legs and immediately hooked up to force transducers. Two contractile periods (separated by 60-min rest) were conducted at 35°C including one under high PO2 (550 torr) and one under low PO2 (40 torr) conditions in a blocked order design. Each muscle was stimulated during the contractile period to produce maximal tetanic contractions at stimulation frequencies that were increased every min until force had dropped to 60% of initial maximum force. RESULTS: The wet weight of EDL and soleus were both significantly lower in the TNF-α (+) mice than those in TNF-α (-) control mice (EDL: 10.8 ± 0.3 vs. 9.3 ± 0.3 mg; Soleus: 10.5 ± 0.2 vs. 9.3 ± 0.5 mg; N=7-9, P <0.05). The maximal force of EDL from TNF-α (+) mice was significantly lower than those in control under both high (233.4 ± 21.4 vs. 167.6 ± 17.9 mN/mm2) and low PO2 conditions (215.5 ± 18.6 vs. 141.1 ± 6.8 mN/mm2, N=7-9, P < 0.05), while there was no difference in the time to fatigue in EDL muscles. The maximal force in soleus from TNF-α (+) mice was significant lower than control under low PO2 (155.6 ± 10.1 vs. 107.5 ± 17.2 mN/mm2, N=7-9, P < 0.05). The time to fatigue was also significantly reduced in soleus from TNF-α (+) mice compared to control under low PO2 (151.5 ± 10.5 vs. 176.2 ± 10.2 sec, N=7-9, P < 0.05). CONCLUSIONS: These results demonstrate that TNF-α upregulation in the lung has profound effects on peripheral skeletal muscle function, and suggests that slow muscle is particularly vulnerable when low PO2 conditions prevail. Supported by NIHHL091830.