Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation

Am J Respir Cell Mol Biol. 2006 Dec;35(6):689-96. doi: 10.1165/rcmb.2006-0103OC. Epub 2006 Jun 22.


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.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Chronic Disease
  • Disease Models, Animal
  • Histones / genetics
  • Histones / metabolism
  • Lung / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology*
  • Muscular Atrophy / etiology
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology
  • Muscular Atrophy / physiopathology*
  • Myoblasts, Skeletal / drug effects
  • Myoblasts, Skeletal / pathology
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Organ Size
  • Pneumonia / complications
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Pneumonia / physiopathology*
  • Promoter Regions, Genetic
  • Pulmonary Surfactant-Associated Protein C / genetics
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / blood
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Regeneration*
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Histones
  • Pulmonary Surfactant-Associated Protein C
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Myosin Heavy Chains