Increased voluntary exercise in mice deficient for tumour necrosis factor-alpha and lymphotoxin-alpha.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Netea
M G
MG
Department of Medicine, Nijmegen University Centre for Infectious Diseases, Nijmegen, The Netherlands.
Kullberg
B J
BJ
Vonk
A G
AG
Verschueren
I
I
Joosten
L A B
LA
van der Meer
J W M
JW
D000818:Animals; D005221:Fatigue / Q000503:physiopathology; D018950:Lipopolysaccharide Receptors / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D010805:Physical Conditioning, Animal / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000378:metabolism
D018950:Lipopolysaccharide Receptors; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha