Abstract
Duchenne muscular dystrophy (DMD) is a devastating genetic muscle disease resulting in progressive muscle degeneration and wasting. Glucocorticoids, specifically prednisone/prednisolone and deflazacort, are commonly used by DMD patients. Emerging DMD therapeutics include those targeting the muscle-wasting factor, myostatin (Mstn). The aim of this study was to investigate how chronic glucocorticoid treatment impacts the efficacy of Mstn inhibition in the D2.mdx mouse model of DMD. We report that chronic treatment of dystrophic mice with prednisolone (Pred) causes significant muscle wasting, entailing both activation of the ubiquitin-proteasome degradation pathway and inhibition of muscle protein synthesis. Combining Pred with Mstn inhibition, using a modified Mstn propeptide (dnMstn), completely abrogates the muscle hypertrophic effects of Mstn inhibition independently of Mstn expression or SMAD3 activation. Transcriptomic analysis identified that combining Pred with dnMstn treatment affects gene expression profiles associated with inflammation, metabolism, and fibrosis. Additionally, we demonstrate that Pred-induced muscle atrophy is not prevented by Mstn ablation. Therefore, glucocorticoids interfere with potential muscle mass benefits associated with targeting Mstn, and the ramifications of glucocorticoid use should be a consideration during clinical trial design for DMD therapeutics. These results have significant implications for past and future Mstn inhibition trials in DMD.
Highlights
Duchenne muscular dystrophy (DMD) is a lethal X-linked degenerative muscle disease caused by loss of dystrophin, a protein required for stabilization of muscle membranes during contraction [1, 2]
The purpose of the current study is to investigate potential interactive effects of Mstn inhibition combined with a chronic glucocorticoid treatment regimen in the mdx mouse model of DMD
The D2.mdx mouse has emerged as a potentially better preclinical model for testing DMD therapeutics than traditional B10.mdx mice [30, 31], due to a more severe and fibrotic phenotype attributed to a polymorphism in latent TGF-β binding protein (LTBP) 4 [32]
Summary
Duchenne muscular dystrophy (DMD) is a lethal X-linked degenerative muscle disease caused by loss of dystrophin, a protein required for stabilization of muscle membranes during contraction [1, 2]. Recent advancements in dystrophin-based therapeutic approaches have led to nonsense mutation [3] and exon skipping [4] therapies in clinic, and approval for dystrophin gene replacement and/or editing based therapies are likely on the horizon [5,6,7]. If successful, these therapeutic strategies essentially will transform DMD into a milder disease, known as Becker’s muscular dystrophy (BMD), caused by truncated dystrophin protein products. In evaluating therapeutics for DMD, the study of potential interactions with glucocorticoid use is an important aspect to consider, as most, if not all, patients in clinical trials are on glucocorticoids
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