Abstract
Duchenne muscular dystrophy (DMD) patients and the dystrophic mdx mouse have an elevated demand for ATP requiring processes, including Ca2+ regulation and skeletal muscle regeneration. As a key substrate for cellular ATP production, altered glycogen metabolism may contribute significantly to dystrophic pathology and explain reports of mild glucose intolerance. We compare the soleus and extensor digitorum longus (EDL) muscles of the mdx mouse during active muscle necrosis (at 28 days) and at 70 days where pathology is stable. We further investigate the impact of taurine (tau) on dystrophic glycogen metabolism to identify if the benefit seen with tau in a previous study (Barker et al. 2017) was in part owed to altered glycogen handling. The soleus muscle of 28‐ and 70‐day‐old mdx mice had elevated glucose transporter type 4 (GLUT4), glycogenin protein abundances and glycogen content compared to WT (C57BL10/ScSn) controls. Mdx tau mice exhibited modestly reduced glycogen compared to their respective mdx group. The EDL muscle of 28 days mdx tau mice had a ~70% increase in glycogenin protein abundance compared to the mdx but 50% less glycogen content. A twofold greater phosphorylated glycogen synthase (p‐GS) and glycogen phosphorylase (p‐GP) protein abundance was observed in the 70‐day‐old mdx soleus muscle than in the 28‐day‐old mdx soleus muscle. Glycogen debranching enzyme (GDE) protein abundance was elevated in both 28‐ and 70‐day‐old mdx soleus muscles compared to WT controls. We identified an increase in proteins associated with glucose uptake and utilization specific to the predominantly slow‐twitch soleus muscle of mdx mice regardless of age and that taurine affords no obvious benefit to glycogen metabolism in the mdx mouse.
Highlights
1:3600–6000 males are born with the fatal neuromuscular disorder Duchenne muscular dystrophy (DMD) (Bushby et al 2010)
There was an approximate 70% increase in the amount of glycogenin protein abundance in the extensor digitorum longus (EDL) muscle from 28 days mdx tau mice compared to the mdx (Fig 2E), 28 days mdx tau mice showed a 50% decrease in muscle glycogen content compared to the mdx despite this increase (Fig. 2E)
We found an increase in mdx mouse skeletal muscle glycogenin protein abundance and glycogen content, and differences in the abundance of glycogen-associated proteins phosphorylated glycogen synthase (p-GS), phosphorylated GP (p-GP) and Glycogen debranching enzyme (GDE) that were predominantly specific to the more oxidative soleus muscle
Summary
1:3600–6000 males are born with the fatal neuromuscular disorder Duchenne muscular dystrophy (DMD) (Bushby et al 2010). DMD is characterized by the absence of the cytoskeletal protein dystrophin, which anchors the contractile apparatus of the skeletal muscle to the extracellular matrix providing myofibers with stability during contraction. Despite the increased demand for ATP requiring processes such as Ca2+ regulation and skeletal muscle regeneration, DMD patients and the similar dystrophindeficient mdx mouse model exhibit impaired energy metabolism with up to 50% reduction in resting ATP levels reported in dystrophic skeletal muscle (Austin et al 1992; Cole et al 2002). DMD patients have been reported to exhibit a decreased resting energy expenditure and this is likely due to the inability to perform functional exercise (Shimizu-Fujiwara et al 2012).
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