Abstract
BackgroundChronic 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.MethodsGuinea 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.ResultsRepeated 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.ConclusionsIn 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.
Highlights
Chronic obstructive pulmonary disease (COPD) is accompanied by pulmonary inflammation and associated with extra-pulmonary manifestations, including skeletal muscle atrophy
In a mouse model of pulmonary inflammation, we recently demonstrated that muscle NF-κB activation was required for the transition from inflammatory- to muscle atrophy signaling [26], suggesting that systemic inflammation contributes to the loss of skeletal muscle mass following acute pulmonary inflammation
The data presented in this study demonstrate that topical application of a Glycogen synthase kinase-3 (GSK-3) inhibitor does not affect pulmonary inflammation, but reduces skeletal muscle atrophy
Summary
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. Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible and persistent airflow limitation and is associated with pulmonary inflammation [1,2,3]. One of the major systemic consequences of COPD is peripheral muscle dysfunction, comprising a loss of muscle strength and endurance, respectively [5,6,7]. Insulin-like growth factor I (IGF-I) and insulin are both anabolic factors that affect cellular protein turnover via a well-characterized signaling conduit that includes phosphorylation of phosphatidylinositol-3 kinase (PI-3K), resulting in the activation of Akt/PKB (hereafter termed Akt) [13]. Akt activation results in the phosphorylation and subsequent cytoplasmic retention of the Forkhead box O (FoXO) class of transcription factors, which have been implicated in the coordination of proteolytic gene expression [14,15,16]
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