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 5

NAM and PN restore MuSC function and enhance regeneration in aged skeletal muscle.

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NAM and PN restore MuSC function and enhance regeneration in aged skelet...
(A and B) Gastrocnemius (A) and plasma (B) concentrations of NAM and PN or NAM and PLP by LC-MS/MS in young and aged mice. N ≥ 12 mice per group.(C) Experimental scheme of CTX-induced muscle regeneration in young and aged mice treated with The NAM/PN combination or vehicle. (D–G) Representative immunofluorescence images (D) and quantification of PAX7+ (E), PAX7+Ki67+ (F), and MYOGENIN+ (G) cells on tibialis anterior (TA) cross-sections from young (N = 5) and aged vehicle- (N = 6) and NAM/PN combination–treated (N = 7) mice at 5 dpi. (H) Gene set enrichment analysis curated from Gene Ontology:Biological Process (GO:BP) gene sets (https://www.gsea-msigdb.org/gsea/msigdb) of freshly isolated MuSCs from young and aged mice (age effect) and of aged MuSCs treated ex vivo with vehicle or the NAM/PN combination (treatment effect) (N = 6). (I) Gene set enrichment analysis of curated Hallmarks gene sets of regenerating GC muscles of young vs. aged mice and of vehicle- vs. NAM/PN combination–treated aged mice 5 dpi (N = 6). False discovery rate, 10%. (J and K) Representative images (J) and quantification (K) of fibrotic aniline blue+ area from a Masson’s trichrome staining of TA cross-sections from young (N = 5) and aged vehicle- (N = 7) and NAM/PN combination–treated (N = 8) mice at 12 dpi. (L–O) Representative immunofluorescence images (L), quantification of minimum ferret myofiber size of small (≤22 μm) (M), intermediate (>22 μm and ≤32 μm) (N), and large (>32 μm) (O) regenerating myofibers in TA cross-sections from young (N = 6) and aged vehicle- (N = 7) and NAM/PN combination–treated (N = 6) mice at 12 dpi. Data are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 with 2-tailed unpaired Student’s t test (A and B) and 1-way ANOVA followed by post hoc Tukey’s (E–G, K, and M–O) multiple comparison tests. Scale bars: 50 μm.