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

Area of Science:

• Biochemistry
• Muscle Physiology
• Pharmacology

Background:

• Duchenne muscular dystrophy (DMD) is a progressive muscle disorder caused by a lack of functional dystrophin.
• Current DMD therapies are limited, especially in mitigating muscle damage from eccentric contractions (ECCs).

Purpose of the Study:

• To investigate if expanding nicotinamide adenine dinucleotide (NAD) pools can therapeutically benefit muscles in dystrophin-deficient mice.
• To compare two small molecule strategies: NAD precursor supplementation and CD38 inhibition.

Main Methods:

• A metabolomics approach was used to analyze muscle phenotypes in dystrophin-deficient (MDX) mice subjected to ECCs.
• Mice were treated with either nicotinamide riboside (NAD precursor) or a CD38 antagonist.

Main Results:

• CD38 antagonist treatment partially normalized the muscle metabolome, particularly pentose phosphate pathway intermediates, unlike nicotinamide riboside.
• Neither strategy led to sustained increases in NAD levels, reduced muscle damage, or improved strength after repeated ECCs.

Conclusions:

• Eccentric injury in DMD leads to chronic NAD depletion, impacting muscle molecular phenotypes.
• While CD38 inhibition is more effective than nicotinamide riboside at addressing molecular changes, neither small molecule approach sufficiently restores muscle function or protects against injury.
• Modulating NAD metabolism alone is insufficient as a therapeutic strategy for DMD.