Netea M G, Kullberg B J, Vonk A G, Verschueren I, Joosten L A B, van der Meer J W M
Department of Medicine, Nijmegen University Centre for Infectious Diseases, Nijmegen, The Netherlands.
Eur J Clin Invest. 2007 Sep;37(9):737-41. doi: 10.1111/j.1365-2362.2007.01851.x.
The endogenous mediators playing a role in the sensing of fatigue and cessation of exercise are yet to be characterized. We hypothesized that proinflammatory cytokines, in particular tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LT) transmit signals leading to fatigue.
Mice were placed in a cage with a freely rotating exercise wheel and allowed to adapt for 24 h. The running distance was measured for two additional periods of 24 h. The effects of the administration of intravenous anti-TNF antibodies, intracerebral recombinant TNF, or intravenous lipopolysaccharide (LPS) were also determined.
Compared to normal littermates, the voluntary daily running distance was 1.8-fold greater in mice with a disruption of the gene for TNFalpha, and 3-fold greater in mice with a gene disruption for both TNFalpha and LT. Intravenous administration of a monoclonal antibody against murine TNFalpha did not affect the running distance of wild-type mice, whereas administration of TNF intracerebrally reduced by 4-fold the voluntary running distance of the animals. This demonstrates that fatigue is mediated by TNFalpha expressed in the central nervous system (CNS) and not by increased peripheral TNFalpha concentrations. TNFalpha and LT are strong inducers of prostaglandins, but mice with disrupted prostaglandin or prostacyclin receptors exhibited running distances not significantly different from their wild-type littermates. Thus, signalling molecules other than prostaglandins mediate the effect of TNFalpha and LT on exercise capacity.
Our finding that exercise capacity is controlled by TNFalpha is the first to define the endogenous mediators of fatigue, and may have important implications for diseases with impaired exercise tolerance.
在疲劳感知和运动停止过程中发挥作用的内源性介质尚未得到明确。我们假设促炎细胞因子，特别是肿瘤坏死因子-α（TNFα）和淋巴毒素-α（LT）传递导致疲劳的信号。
将小鼠置于带有自由旋转运动轮的笼子中，使其适应24小时。在另外两个24小时时间段内测量跑步距离。还确定了静脉注射抗TNF抗体、脑内注射重组TNF或静脉注射脂多糖（LPS）的效果。
与正常同窝小鼠相比，TNFα基因缺失的小鼠每日自愿跑步距离增加了1.8倍，TNFα和LT基因均缺失的小鼠增加了3倍。静脉注射抗小鼠TNFα单克隆抗体不影响野生型小鼠的跑步距离，而脑内注射TNF使动物的自愿跑步距离减少了4倍。这表明疲劳是由中枢神经系统（CNS）中表达的TNFα介导的，而不是外周TNFα浓度升高所致。TNFα和LT是前列腺素的强诱导剂，但前列腺素或前列环素受体缺失的小鼠的跑步距离与野生型同窝小鼠无显著差异。因此，除前列腺素外的信号分子介导了TNFα和LT对运动能力的影响。
我们发现运动能力受TNFα控制，这首次明确了疲劳的内源性介质，可能对运动耐力受损的疾病具有重要意义。
