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Published ahead of print on June 22, 2006, doi:10.1165/rcmb.2006-0103OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 35, pp. 689-696, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2006-0103OC

Muscle Wasting and Impaired Muscle Regeneration in a Murine Model of Chronic Pulmonary Inflammation

Ramon C. J. Langen, Annemie M. W. J. Schols, Marco C. J. M. Kelders, Jos L. J. van der Velden, Emiel F. M. Wouters and Yvonne M. W. Janssen-Heininger

Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands; and Department of Pathology, University of Vermont, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Ramon Langen, Maastricht University, Department of Respiratory Medicine, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: r.langen{at}pul.unimaas.nl

Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-{alpha}, are common features of chronic obstructive pulmonary disease. To investigate whether inflammation of the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed overexpression of a TNF-{alpha} transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-{alpha} mice exhibited increased levels of TNF-{alpha} in the circulation and increased endogenous TNF-{alpha} expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-{alpha}. Decreased muscle and body weights observed in SP-C/TNF-{alpha} mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF-{alpha} mouse musculature revealed a decreased muscle regenerative capacity, shown by attenuated myoblast proliferation and differentiation in response to reloading of disuse-atrophied muscle, which may contribute to skeletal muscle wasting. Importantly, incubation of cultured myoblasts with TNF-{alpha} also resulted in elevated TNF-{alpha} mRNA levels and inhibition of myoblast differentiation. Collectively, our results demonstrate that chronic pulmonary inflammation results in muscle wasting and impaired muscle regeneration in SP-C/TNF-{alpha} mice, possibly as a consequence of an amplificatory TNF-{alpha} expression circuit extending from the lung to skeletal muscle.

Key Words: muscle regeneration • pulmonary inflammation • skeletal muscle atrophy • TNF-{alpha} •


CLINICAL RELEVANCE

This work adds to the understanding of how pulmonary inflammation results in systemic pathology and can direct further research aimed at prevention of the disabling consequences of skeletal muscle atrophy in disease conditions such as COPD.

 



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