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
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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

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Figure 1

A high-content screen identifies NAM and PN as activators of hMP amplification and differentiation.

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A high-content screen identifies NAM and PN as activators of hMP amplifi...
(A) Percentage of PAX7–MYOD+ hMPs after 72-hour treatment with 50,000 bioactive molecules. Min-max normalization between negative (black line) and positive control (LY363947, green line) was performed. Blue, compounds with normalized effect size >15%; black, GRAS molecules; red, GRAS hits. (B) Relative number of PAX7–MYOD+ cells in hMPs treated with GRAS-classified molecules. n = 2–4 cell culture replicates from N = 2 donors. (C) Representative images of hMPs treated with vehicle, NAM, or PN for 72 hours. Scale bar: 100 μm. (D and E) Dose response of NAM and PN on the relative number of PAX7–MYOD+ (D) and PAX7+ (E) hMPs treated with vehicle, NAM, or PN for 72 hours. n ≥ 21 cell culture replicates from N = 2 donors. (F–H) Gene set enrichment analysis of upregulated gene sets in hMPs treated with NAM (F), PN (G), or the NAM/PN combination (H) compared with vehicle. False discovery rate, 10%. N = 5 donors. (I) Venn diagram of upregulated genes using 5% FDR multiple testing correction. (J) Dose response of NAM, PN, and the NAM/PN combination on PAX7–MYOD+ hMPs. n ≥ 6 cell culture replicates from 1 donor. (K) Quantification of PAX7+ hMPs after vehicle and NAM/PN combination treatment. n ≥ 32 cell culture replicates from 1 donor. (L–O) Representative images (L) and quantification of nuclei within myotubes (M), myotube area (N), and fusion index (O) in hMPs treated with vehicle or NAM/PN combination during proliferation and differentiation. Scale bar: 500 μm. n ≥ 28 cell culture replicates for each condition from 1 donor. (P) Quantification of PAX7+ hMPs after vehicle and NAM/PN combination treatment after myotube differentiation induction. n ≥ 92 cell culture replicates from 1 donor. Data are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 with 1-way ANOVA followed by post hoc Dunnett’s (D and E) or Tukey’s (J) multiple comparison test and 2-tailed unpaired Student’s t tests (K and M–P).