Inhibition of CD38 promotes muscle regeneration

抄録

Sarcopenia is aging-related progressive loss of skeletal muscle mass and strength, which is associated with decreased quality of life and increased mortality. Aging-related decline of muscle regeneration is a risk factor for the onset of sarcopenia.

Nicotinamide adenine dinucleotide (NAD⁺) is considered as an anti-aging molecule which can suppress the onset of aging-related diseases. NAD⁺ is an essential molecule for all living organisms, which is associated with multiple biological processes, including energy production, DNA repair, and protein modifications. NAD⁺ levels in tissues decrease with aging, which leads functional loss of tissues. On the other hand, NAD⁺ repletion is considered to have therapeutic potential against aging-related diseases. For example, treatment of NAD⁺ precursor is reported to suppress loss of muscle function caused by aging, which is lead by the increase in NAD⁺ levels.

Increased degradation of NAD⁺ is the cause of decreased NAD⁺ levels during aging. CD38 is the enzyme which degrades NAD⁺, and expression levels of CD38 increase with aging. NAD⁺ decline caused by CD38 leads multiple aging signatures, such as delayed metabolism, cell senescence, and tissue fibrosis. Importantly, inhibition or genetic loss of CD38 can remarkably increase NAD⁺ levels in tissues. Additionally, inhibition of CD38 improves muscle function in aged animals. Therefore, CD38 is an attractive target against the onset of sarcopenia.

In this research, we investigated the effect of inhibition or genetic loss of CD38 on muscle regeneration. Genetic deletion of CD38 reduced muscle fibrosis and improved recovery of muscle after the treatment of cardiotoxin. Furthermore, inhibition of CD38 increased NAD⁺ levels and promoted myoblast differentiation. These results suggest that inhibition of CD38 has therapeutic potential against the onset of sarcopenia.