Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-α, 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-α transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-α mice exhibited increased levels of TNF-α in the circulation and increased endogenous TNF-α expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-α. Decreased muscle and body weights observed in SP-C/TNF-α mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF-α 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-α also resulted in elevated TNF-α 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-α mice, possibly as a consequence of an amplificatory TNF-α expression circuit extending from the lung to skeletal muscle.