NAD⁺ level at a young age affects skeletal muscle functions at an old age

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is an essential coenzyme involved in many cellular functions including energetics, circadian rhythm, transcription, and epigenetics etc. Imbalanced NAD⁺ levels lead to age-related pathologies. NAD⁺ is biosynthesized by de novo, Preiss-Handler, and salvage pathways. It has been shown that the salvage pathway is more vital in maintaining NAD⁺ levels in skeletal muscle. Whereas evidence proving the role of de novo and Preiss-Handler pathways remains elusive. NAD synthetase (NADS) is the last enzyme shared in de novo and Preiss-Handler pathways. In this study, we generated NADS KO mice and investigated the role of de novo and Preiss-Handler pathways in skeletal muscle. The skeletal muscle in NADS KO mice showed depleted NAD⁺ levels at a young age resulting in poor skeletal muscle performance assessed by grip strength and endurance on the treadmill. Histology of these mice showed decreased cross-sectional area resembling sarcopenia. Interestingly, old NADS KO mice restored NAD⁺ levels but these mice didn’t recover muscle strength and endurance suggesting that reduced NAD⁺ levels in young age influence exercise performance in old age. Further, RNA sequencing of skeletal muscle revealed circadian genes are altered in NADS KO mice. In addition, we found that NAD+ precursor replenishment rescued the NAD⁺ levels and muscle weakness in NADS KO mice. This study implies that maintaining NAD⁺ levels in young age is crucial in preventing skeletal muscle aging.