Muscle wasting and increased circulating levels of inflammatory cytokines, including tumor necrosis factor alpha (TNF) are common features of COPD. To investigate if inflammation of the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed over-expression of a TNF transgene controlled by the surfactant protein C (SP-C) promoter. Compared to wild type, SP-C/TNF mice exhibited increased levels of TNF in the circulation and increased endogenous TNF expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF. Decreased muscle and body weights observed in SP-C/TNF mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF mouse musculature revealed a decreased muscle regenerative capacity, evidenced 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 also resulted in elevated TNF 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 mice, possibly as a consequence of an amplificatory TNF expression circuit extending from the lung to skeletal muscle.