Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: II. Effects on skeletal muscle atrophy

Respiratory Research

Ramon CJ Langen²  Reinoud Gosens¹  Annemie MWJ Schols²  Chiel C de Theije²  Astrid Haegens²  Alexander HV Remels²  Hoeke A Baarsma¹  Nicholas AM Pansters²  Koen JP Verhees² 

[1] Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, The Netherlands;Department of Respiratory Medicine, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre + (MUMC+), PO box 5800, 6202, AZ Maastricht, The Netherlands

关键词: Myogenesis;    Skeletal muscle atrophy;    LPS;    Inflammation;    COPD;   

Others  :  792425
DOI  :  10.1186/1465-9921-14-117

 received in 2013-05-15, accepted in 2013-10-14,  发布年份 2013

【 摘 要 】

Background

Chronic obstructive pulmonary disease (COPD) is accompanied by pulmonary inflammation and associated with extra-pulmonary manifestations, including skeletal muscle atrophy. Glycogen synthase kinase-3 (GSK-3) has been implicated in the regulation of muscle protein- and myonuclear turnover; two crucial processes that determine muscle mass. In the present study we investigated the effect of the selective GSK-3 inhibitor SB216763 on muscle mass in a guinea pig model of lipopolysaccharide (LPS)-induced pulmonary inflammation-associated muscle atrophy.

Methods

Guinea pigs were pretreated with either intranasally instilled SB216763 or corresponding vehicle prior to each LPS/saline challenge twice weekly. Pulmonary inflammation was confirmed and indices of muscle mass were determined after 12 weeks. Additionally, cultured skeletal muscle cells were incubated with tumor necrosis factor α (TNF-α) or glucocorticoids (GCs) to model the systemic effects of pulmonary inflammation on myogenesis, in the presence or absence of GSK-3 inhibitors.

Results

Repeated LPS instillation induced muscle atrophy based on muscle weight and muscle fiber cross sectional area. Intriguingly, GSK-3 inhibition using SB216763 prevented the LPS-induced muscle mass decreases and myofiber atrophy. Indices of protein turnover signaling were unaltered in guinea pig muscle. Interestingly, inhibition of myogenesis of cultured muscle cells by TNF-α or synthetic GCs was prevented by GSK-3 inhibitors.

Conclusions

In a guinea pig model of LPS-induced pulmonary inflammation, GSK-3 inhibition prevents skeletal muscle atrophy without affecting pulmonary inflammation. Resistance to inflammation- or GC-induced impairment of myogenic differentiation, imposed by GSK-3 inhibition, suggests that sustained myogenesis may contribute to muscle mass maintenance despite persistent pulmonary inflammation. Collectively, these results warrant further exploration of GSK-3 as a potential novel drug target to prevent or reverse muscle wasting in COPD.

【 授权许可】

   
2013 Verhees et al.; licensee BioMed Central Ltd.

【 图 表 】

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