Nicotinamide Phosphoribosyltransferase-elevated NAD+ biosynthesis prevents muscle disuse atrophy by reversing mitochondrial dysfunction

Abstract

Background: It is well known that muscle disuse atrophy is associated with mitochondrial dysfunction, which is implicated in reduced nicotinamide adenine dinucleotide (NAD⁺ ) levels. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in NAD⁺ biosynthesis, may serve as a novel strategy to treat muscle disuse atrophy by reversing mitochondrial dysfunction.

Methods: To investigate the effects of NAMPT on the prevention of disuse atrophy of skeletal muscles predominantly composed of slow-twitch (type I) or fast-twitch (type II) fibres, rabbit models of rotator cuff tear-induced supraspinatus muscle atrophy and anterior cruciate ligament (ACL) transection-induced extensor digitorum longus (EDL) atrophy were established and then administered NAMPT therapy. Muscle mass, fibre cross-sectional area (CSA), fibre type, fatty infiltration, western blot, and mitochondrial function were assayed to analyse the effects and molecular mechanisms of NAMPT in preventing muscle disuse atrophy.

Results: Acute disuse of the supraspinatus muscle exhibited significant loss of mass (8.86 ± 0.25 to 5.10 ± 0.79 g; P < 0.001) and decreased fibre CSA (3939.6 ± 136.1 to 2773.4 ± 217.6 μm² , P < 0.001), which were reversed by NAMPT (muscle mass 6.17 ± 0.54 g, P = 0.0033; fibre CSA, 3219.8 ± 289.4 μm² , P = 0.0018). Disuse-induced impairment of mitochondrial function were significantly improved by NAMPT, including citrate synthase activity (40.8 ± 6.3 to 50.5 ± 5.6 nmol/min/mg, P = 0.0043), and NAD⁺ biosynthesis (279.9 ± 48.7 to 392.2 ± 43.2 pmol/mg, P = 0.0023). Western blot revealed that NAMPT increases NAD⁺ levels by activating NAMPT-dependent NAD⁺ salvage synthesis pathway. In supraspinatus muscle atrophy due to chronic disuse, a combination of NAMPT injection and repair surgery was more effective than repair in reversing muscle atrophy. Although the predominant composition of EDL muscle is fast-twitch (type II) fibre type that differ from supraspinatus muscle, its mitochondrial function and NAD⁺ levels are also susceptible to disuse. Similar to the supraspinatus muscle, NAMPT-elevated NAD⁺ biosynthesis was also efficient in preventing EDL disuse atrophy by reversing mitochondrial dysfunction.

Conclusions: NAMPT-elevated NAD⁺ biosynthesis can prevent disuse atrophy of skeletal muscles that predominantly composed with either slow-twitch (type I) or fast-twitch (type II) fibres by reversing mitochondrial dysfunction.

Keywords: Fatty infiltration; Mitochondrial dysfunction; Muscle disuse atrophy; NAMPT; Rotator cuff tear.