Complementary NAD + replacement strategies fail to functionally protect dystrophin-deficient muscle

Duchenne 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 mechanica...

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Bibliographic Details
Published in:	Skeletal muscle Vol. 10; no. 1; p. 30
Main Authors:	Frederick, David W, McDougal, Alan V, Semenas, Melisa, Vappiani, Johanna, Nuzzo, Andrea, Ulrich, John C, Becherer, J David, Preugschat, Frank, Stewart, Eugene L, Sévin, Daniel C, Kramer, H Fritz
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 22-10-2020 BioMed Central BMC
Subjects:	Adenine ADP-ribosyl cyclase ADP-ribosyl Cyclase 1 - antagonists & inhibitors Amino acids Animals CD38 CD38 antigen Degeneration Duchenne's muscular dystrophy Dystrophin Dystrophin - deficiency Eccentric Enzymatic activity Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Enzymes Health aspects Injury Intermediates Male MDX Membrane Glycoproteins - antagonists & inhibitors Metabolism Metabolites Metabolome Metabolomics Mice Mice, Inbred C57BL Mice, Inbred mdx Muscle Contraction Muscle, Skeletal - drug effects Muscle, Skeletal - metabolism Muscle, Skeletal - physiology Muscular Dystrophy, Duchenne - drug therapy Muscular Dystrophy, Duchenne - genetics Muscular Dystrophy, Duchenne - metabolism Musculoskeletal system Mutation NAD NAD - metabolism Niacinamide Niacinamide - analogs & derivatives Niacinamide - pharmacology Niacinamide - therapeutic use Pentose phosphate pathway Phenotypes Phosphates Physiological aspects Polyamines Principal components analysis Pyridinium Compounds - pharmacology Pyridinium Compounds - therapeutic use Recovery of function Rodents Utrophin MDX NAD Metabolomics NR Injury Therapeutics CD38 Eccentric
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Summary:	Duchenne 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). Using 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. Administering 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. In 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2044-5040 2044-5040
DOI:	10.1186/s13395-020-00249-y