Muscle cells rely on a molecule called NAD+ to sense and respond to metabolic stress from exercise, diet, or ageing, and a newly identified protein—NMRK2—appears to be the master switch that controls NAD+ levels specifically in skeletal muscle. This matters because NAD+ levels decline with age, and that drop is linked to loss of insulin sensitivity, reduced mitochondrial function, and impaired muscle repair. Current strategies to boost NAD+—such as supplements—work throughout the body, but they may miss the muscle-specific bottleneck. The researchers have discovered that NMRK2 acts as a dedicated salvage mechanism, recycling NAD+ precursors directly inside muscle cells. If NMRK2 is the rate-limiting step, then targeting it could offer a far more precise way to restore metabolic health in ageing muscle. This is fundamental science. If the project succeeds, it will provide a mechanistic blueprint for how muscle maintains its NAD+ supply under different conditions—dietary restriction, high-fat feeding, or exercise. That knowledge could eventually lead to pharmaceutical or dietary interventions that boost muscle NAD+ without affecting other tissues, potentially improving metabolic health in older adults or people with muscle-wasting diseases.
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Homeostasis relies on the ability of muscle to sense redox balance during metabolic stresses such as exercise, nutrient availability, or aging, and make the requisite adaptations. Consumption of NAD+ by redox sensing protein deacetylases (the sirtuins) can modulate numerous metabolic processes such as insulin sensitivity, glucose transport, mitochondrial biogenesis, and muscle satellite cell function. Therefore, pharmacological and nutritional strategies aimed at increasing NAD+ in skeletal musc le represent an innovative treatment strategy for numerous diseases of ageing. We have identified nicotinamide riboside kinase 2 (NMRK2) as a novel, muscle-specific, NAD+ salvage mechanism that directly regulates NAD+ generation in vitro and in in vivo genetic models. Based on this novel data, we propose that NMRK2 is a rate-limiting step in the maintenance of NAD+ in skeletal muscle and as such is a principal regulator of skeletal muscle adaptation to age and exercise. To test this hypothesi s, this project will utilize cellular in vitro and novel in vivo mouse models to establish the role of NMRK2/NAD+ salvage mechanisms in skeletal muscle metabolic homeostasis and following interventions such as dietary restriction, high-fat feeding and exercise training. Key outcomes: 1. Detailed mechanistic insight into NMRK2 and its role in NAD+ salvage and metabolic adaptation in muscle. 2. Systems approaches will relate NMRK2 pathway activity to other strategies used by muscle to salvage NAD+, and identify mechanisms establishing its bioavailability in ageing and exercise models. 3. Identify therapeutically relevant insight for pharmaceutical or dietary manipulation of NAD+ salvage pathways.
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