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 2

The combination of NAM and PN enhances MuSC function in vivo and increases muscle strength during regeneration.

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The combination of NAM and PN enhances MuSC function in vivo and increas...
(A–D) Representative immunofluorescence images and quantification of FACS-isolated mouse MuSCs treated with vehicle or NAM/PN combination ex vivo for 4 days. n = 6 cell culture replicates with cells pooled from N = 4 mice. (E) Cardiotoxin-induced muscle regeneration in young mice treated orally with NAM/PN combination or vehicle. (F and G) NAM and PN concentrations quantified by LC-MS/MS in uninjured gastrocnemius (GC) muscles from young vehicle- (N = 9) and NAM/PN combination–treated (N = 8) mice. (H–K) Representative immunofluorescence images (H) and quantification of PAX7+ (I), PAX7+Ki67+ (J), and MYOGENIN+ (K) cells in tibialis anterior (TA) cross-sections from vehicle- (N = 6) and NAM/PN combination–treated (N = 5) mice at 5 dpi. (L) Number of PAX7+ sublaminar MuSCs in TA cross-sections from vehicle- (N = 6) and NAM/PN combination–treated (N = 6) mice at 12 dpi. (M–P) Representative immunofluorescence images (M) and quantification of minimum ferret of small (≤33 μm) (N), intermediate (>33 μm and ≤43 μm) (O), and large (>43 μm) (P) regenerating myofibers in TA cross-sections from vehicle- (N = 5) and NAM/PN combination–treated (N = 6) mice at 12 dpi. (Q) Eccentric contraction–induced (EC-induced) muscle regeneration after electrically evoked lengthening contractions of plantar flexor (PF) muscles in young vehicle- and NAM/PN combination–treated mice. (R–U) Representative immunofluorescence (R) and quantification of PAX7+ (S), Ki67+ (T), and MYOGENIN+ (U) cells in GC muscle from vehicle- (N = 5) and NAM/PN combination–treated (N = 5) mice 7 days after the EC protocol. (V) Quantification of muscle strength (single twitch peak torque) in PF muscles before and 1, 7, and 14 days after EC-induced injury. N = 12 mice. Data are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 with 2-tailed unpaired Student’s t tests (B–D, F, G, I–L, N–P, and S–V). Scale bars: 50 μm.