• Experimentally increasing brain NMN transporter Slc12a8 improves muscle function in aged mice, while reducing NMN transporters in young mice induces muscle decline.
  • These findings suggest an important NMN-mediated connection between the brain and muscle that drives age-related muscle decline (sarcopenia).

As we grow older, loss of muscle mass and strength – sarcopenia – facilitates physical decline, sedentary behavior, and cognitive impairment. Researchers still don’t understand the processes that underlie sarcopenia, and so far, no drugs have been identified to target this debilitating aspect of aging.

Imai and colleagues from the Washington University School of Medicine show in Cell Reports that a nicotinamide mononucleotide (NMN) transporter (Slc12a8) in the brain maintains the metabolism of muscle. They show that experimentally reducing the abundance of brain NMN transporters in young and middle-aged mice recapitulates the fatigued and weakened muscles found in aged mice. The St. Louis-based research team goes on to show that experimentally doubling the abundance of the transporters in aged mice improves sarcopenia, restoring more youthful muscle function. These findings suggest the existence of a pathway for muscle function that depends on NMN transporters in the brain to maintain NAD+ levels, which drives sarcopenia. 

Reduced Brain NMN Transporters Contribute to Sarcopenia

Research has shown that the age-related decline in NAD+ levels is associated with sarcopenia. Imai and colleagues recently found that NMN transporters – proteins that transport NMN into cells – maintain NAD+ levels during aging, prompting them to examine the link between these NMN transporters and their influence on sarcopenia. By doubling NMN transporter abundance in aged mouse brains, the team found that this procedure drastically improved muscle strength and endurance and enhanced muscle utilization of carbohydrates. These results indicate that increasing the abundance of NMN transporters in the brain of aged mice can extensively alleviate sarcopenia by restoring muscle metabolism and function.

(Ito et al., 2022 | Cell Reports) Doubling Brain NMN transporters reverse signs of sarcopenia. Increasing the abundance of NMN transporters (Slc12a8, red) enhances endurance (Figure E), glycolysis (Figure F), and muscle strength (measured in millinewtons of force) upon repeated stimulation (Figure I) in aged mice.

To confirm the role of brain NMN transporters in muscle function, Imai and colleagues experimentally reduced NMN transporters by about 40% in the brains of young and middle-aged mice. They found that the young mice exhibited reduced muscle strength and endurance, similar to aged mice with sarcopenia. The researchers also showed that the amount of carbohydrates expended for muscle energy declines when the NMN transporter abundance is reduced, indicating that NMN transporters affect carbohydrate metabolism. These findings show that the age-related decline in brain NMN transporters instigates muscle weakness, impaired endurance, and abnormal muscle metabolism, suggesting that these transporters contribute to sarcopenia.

“Our results highlight a key role of Slc12a8 in the [brain] for regulation of energy metabolism and skeletal muscle functions and imply its importance in the pathogenesis of sarcopenia and frailty during aging,” said Imai and colleagues.

Can NMN Supplementation Counter Transporter Loss and Alleviate Age-Related Muscle Deterioration?

This study provides the first evidence of a functional link between the Slc12a8 NMN transporter and the onset of sarcopenia. Figuring out how to increase NMN transporter abundance in the brain during aging with genetic medicines or stimulating the NMN transporter with pharmaceuticals could give new ways to alleviate sarcopenia in aging individuals.

Studies have shown that supplementing rodents with NMN restores their muscle function and alleviates sarcopenia. A clinical trial has shown that NMN boosts insulin sensitivity in the muscles of postmenopausal women, which improves glucose utilization (metabolism). However, longer-term studies in aged humans must be performed to find out whether NMN alone can improve muscle performance to overcome sarcopenia. If not, future treatments could entail finding ways to increase the numbers of Slc12a8 transporters in the brain.