Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging
Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E. Jacot, Thibaut Desgeorges, José L. Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G. Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N. Feige
Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E. Jacot, Thibaut Desgeorges, José L. Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G. Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N. Feige
View: Text | PDF
Research Article Muscle biology

Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging

Abstract

Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have a history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM and PN accelerated muscle regeneration in vivo by stimulating MuSCs, increased muscle strength during recovery, and overcame MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously declined during aging in model organisms and interindependently associated with muscle mass and walking speed in a cohort of 186 aged people. Collectively, our results establish the NAM/PN combination as a nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.

Authors

Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E. Jacot, Thibaut Desgeorges, José L. Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G. Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N. Feige

×

Figure 6

Nicotinamide and pyridoxine associate with muscle mass and function in aged humans and restore the myogenic capacity of aged hMPs.

Options: View larger image (or click on image) Download as PowerPoint
Nicotinamide and pyridoxine associate with muscle mass and function in a...
(A–D) LC-MS/MS analyses of NAM and pyridoxal-5′-phosphate (PLP; bioactive pyridoxine) in the sera of men aged >60 years (N = 186 participants). Appendicular lean mass index (ALMi) (A) and gait speed (B) were correlated to serum concentrations of NAM and PLP using a linear regression model adjusted for age. Regression line (black) and 95% confidence interval (CI) (gray). Estimated outcomes of the combined effect of NAM and PLP on ALMi (C) and gait speed (D) were modeled at different ages using a multiple linear regression model adjusted for age. (E–H) Representative immunofluorescence images (E) and quantification of PAX7+ (F), Ki67+ (G), and MYOD+ (H) hMPs. n ≥ 8 cell culture replicates from N = 8 donors aged from 18 to 92 years following 72 hours of treatment with vehicle or the NAM/PN combination. Data are shown as the mean ± SEM. **P < 0.01; ***P < 0.001 with Brown-Forsythe and Welch’s ANOVA tests with Dunnett’s T3 multiple-comparison in 8 donors (F–H). Data are shown as the mean ± SEM. Scale bar: 100 μm.