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Abstract
Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by mutations in the gene responsible for dystrophin production
Accumulating evidence suggests that defects in muscle satellite cells (SCs) contribute to the dystrophic state by limiting skeletal muscle repair and regeneration [20,21]
Overall we show that longer chain acylcarnitines can impair adipose progenitor cell (APC) proliferation, demonstrating that metabolic alterations associated with muscular dystrophy can extend beyond skeletal muscle to other non-muscle cell types
Summary
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by mutations in the gene responsible for dystrophin production. Patients with DMD typically experience progressive loss of skeletal muscle; leaving them symptomatic by age 5, wheelchair bound by age 12, and often deceased within the second decade of life [2]. In contrast to the human disorder, MDX mice only exhibit slightly reduced lifespans when compared to wildtype (WT) mice [7] and the mice retain skeletal muscle functionality throughout life. This discrepancy (or milder disease phenotype) is thought to be due to compensation by the related structural protein utrophin in mice [8,9]
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