Abstract
BackgroundDuchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs).MethodsUsing a metabolomics-based approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most chronically depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit using two complementary small molecule strategies: provision of a biosynthetic precursor, nicotinamide riboside, or specific inhibition of the NAD-degrading ADP-ribosyl cyclase, CD38.ResultsAdministering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, with a pronounced impact on intermediates of the pentose phosphate pathway, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy sustainably increased the bulk tissue NAD pool, lessened muscle damage markers, nor improved maximal hindlimb strength following repeated rounds of eccentric challenge and recovery.ConclusionsIn the absence of dystrophin, eccentric injury contributes to chronic intramuscular NAD depletion with broad pleiotropic effects on the molecular phenotype of the tissue. These molecular consequences can be more effectively overcome by inhibiting the enzymatic activity of CD38 than by supplementing nicotinamide riboside. However, we found no evidence that either small molecule strategy is sufficient to restore muscle contractile function or confer protection from eccentric injury, undermining the modulation of NAD metabolism as a therapeutic approach for DMD.
Highlights
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin
In the absence of dystrophin, eccentric injury contributes to chronic intramuscular nicotinamide adenine dinucleotide (NAD) depletion with broad pleiotropic effects on the molecular phenotype of the tissue. These molecular consequences can be more effectively overcome by inhibiting the enzymatic activity of CD38 than by supplementing nicotinamide riboside
Dystrophin deficiency alters the muscle NAD metabolome and energy producing pathways To assess the biochemical adaptations of muscle to dystrophin deficiency, we analyzed the gastrocnemius muscles of MDX mice before and after eccentric challenge using an untargeted metabolic profiling platform
Summary
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Dystrophinopathies are a class of diseases manifesting primarily in skeletal muscle and caused by a variety of mutations in the 2.4 Mb dystrophin gene which render the dystrophin protein inactive. In patients with Duchenne muscular dystrophy (DMD), the absence of functional dystrophin leads to limb muscle weakness, followed by gradual muscle atrophy, cardiomyopathy, and premature death. Though progress has been made in addressing the primary defects in dystrophin via exon skipping or gene-replacement therapies [2], means of mitigating the effects of eccentric injuries to the muscle of DMD patients have primarily been limited to treatment with palliative anti-inflammatory drugs
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