NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Neuromuscular diseases cause progressive muscle weakness due to inherited mutations.
• Nicotinamide adenine dinucleotide (NAD+) is crucial for cellular energy and function.
• Mitochondrial dysfunction and altered NAD+ metabolism are implicated in muscle degeneration.

Purpose of the Study:

• To investigate the role of NAD+ in protecting skeletal muscle from degeneration.
• To explore NAD+ replenishment as a therapeutic strategy for muscular dystrophies.

Main Methods:

• Analysis of skeletal muscle transcriptomes in healthy mice and patients with muscular dystrophy.
• Measurement of NAD+ levels, poly(ADP)-ribose polymerase (PARP) activity, and enzyme expression in mouse models.
• Dietary supplementation with nicotinamide riboside in mouse and C. elegans models of Duchenne's muscular dystrophy (DMD).

Main Results:

• Skeletal muscle transcriptomes in DMD patients showed enrichment for NAD+-consuming enzymes (PARPs, NNMT).
• MDX mice (a DMD model) exhibited reduced NAD+ levels, increased PARP activity, and decreased NAMPT expression.
• Nicotinamide riboside supplementation improved muscle function, cardiac pathology, mitochondrial function, and reduced inflammation and fibrosis in DMD models.

Conclusions:

• NAD+ depletion and increased PARP activity are features of muscular dystrophy.
• NAD+ replenishment demonstrates therapeutic potential for neuromuscular degenerative diseases.
• Targeting NAD+ metabolism may offer a novel treatment strategy for conditions like DMD.