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

Abstract

Zuo L, Nogueira L, Hogan MC. Effect of pulmonary TNF-␣ 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-␣ 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-␣ in the lung (Tg ϩ ) to test the hypothesis that chronic exposure to TNF-␣ (as seen in COPD) reduces skeletal muscle force production and fatigue resistance, particularly under low PO 2 conditions. At 7-12 mo, body and muscle weight of both extensor digitorum longus (EDL) and soleus were significantly smaller in Tg ϩ compared with littermate wild-type (WT) mice; however, the bodyto-muscle weight ratio was not different between groups. EDL and soleus muscles were subjected to in vitro fatiguing contractile periods under high (ϳ550 Torr) and low PO 2 (ϳ40 Torr). Although all muscles were less fatigue-resistant during low PO 2 compared with high PO 2, only the soleus fatigued more rapidly in Tg ϩ mice (ϳ12%) compared with WT at high PO 2. The maximal tension of EDL was equally reduced in Tg ϩ mice (28 -34% decrease from WT under both PO 2 conditions); but for soleus this parameter was smaller only under low PO 2 in Tg ϩ mice (ϳ31% decrease from WT). The peak rate of relaxation and the peak rate of contraction were both significantly reduced in Tg ϩ EDL muscles compared with WT EDL under low PO 2 conditions, but not in soleus. These results demonstrate that TNF-␣ upregulation in the lung impairs peripheral skeletal muscle function but affects fast-and slow-twitch muscles differentially at high and low PO 2.

One-year mortality after severe COPD exacerbation in Bulgaria

“…An interesting hypothesis on molecular level is increased reactive oxygen species formation and oxidative stress (Zuo et al, 2012). This could lead to increased TNF α levels, which reduce skeletal muscle force and resistance to fatigue (Zuo, Nogueira & Hogan, 2011). As a systemic inflammatory disorder, COPD is associated with respiratory muscle dysfunction (Wouters, 2002) which could be further worsened by this mechanism and contribute to the mortality.…”

Cytokine Signaling in Skeletal Muscle Wasting

“…So the question is whether circulating or lung-derived TNF-/ would have an impact on muscle function. In a transgenic mouse model overexpressing TNF-/ in the lung, TNF-/ impaired peripheral skeletal muscle function due to excessive formation of superoxide in contracting skeletal muscle [36,37]. However, a study of 426 COPD patients over a 3-year period found that TNF-/ levels were associated with muscle loss only in patients who were cachectic at entry into the study; the authors concluded that inflammation is a consequence rather than a cause of initial loss of fat-free mass [38].…”

Superoxide release from contracting skeletal muscle in pulmonary TNF-α overexpression mice

“…It appears that this cytokine may be a key factor in reducing contractile function of the heart, diaphragm, and limb muscles (28,45,59). Specifically, pulmonary TNF-␣ overexpression has been shown to induce peripheral skeletal muscle dysfunction (60) and impair muscle regeneration (27). However, the mechanism by which this occurs has not been fully elucidated.…”

“…Therefore, we have investigated the potential link between TNF-␣ and ROS formation in skeletal muscle. We used a pulmonary TNF-␣ overexpression (Tg ϩ ) mouse to model COPD conditions, as previously described (16,60), and to delineate the role of ROS in a contracting peripheral skeletal muscle (soleus) affected by TNF-␣ overexpression in the lung.…”

“…Therefore, it is important to evaluate skeletal muscle ROS generation in a model of pulmonary TNF-␣ overexpression. In the current study, we used an in vitro soleus muscle model from transgenic (Tg ϩ , pulmonary TNF-␣ overexpression) mice, which mimics many of the pathophysiological conditions of COPD (16,60). We tested the hypothesis that pulmonary TNF-␣ overexpression would increase ROS release from skeletal muscle and decrease fatigue resistance.…”