Targeting Muscle Stem Cells during Aging: from Mechanisms to the Discovery & Clinical Validation of Nutritional Activators

Abstract:
The regenerative capacity of skeletal muscle relies on the activity of Muscle Stem Cells (MuSCs), a population of resident stem cells that enables myofiber repair following intense exercise or injuries, and contributes to tissue homeostasis and turnover. Aging and muscle diseases impair MuSC function, leading to altered regenerative capacity and progressive loss of skeletal muscle mass and strength.
In a first project, we generated a novel StemRep dual color Pax7 and Myf5 in vivo reporter mouse model to investigate MuSC heterogeneity. High levels of Pax7 protein and low levels of Myf5 delineate a deeply quiescent MuSC subpopulation with higher asymmetric division and distinct dynamics of activation, proliferation, and commitment. Aging primarily reduces the Myf5Low MuSCs and skews the stem cell pool towards Myf5High cells with lower quiescence and self-renewal capacity. Altogether, we establish the StemRep model as a versatile tool to study MuSC heterogeneity and broaden our understanding of the function of Myf5 in regulating MuSC quiescence and self-renewal in homeostatic, regenerating, and aged muscles.
In a second project, we used a high-content imaging screen of natural molecules to identify nicotinamide (NAM) and pyridoxine (PN) as potent bioactive nutrients from vitamin B metabolism that synergistically stimulate MuSC activity, while having a history of safe human use. In human clinical cohorts or preclinical models, endogenous levels of NAM and bioactive PN decline during aging and inter-independently associate with muscle mass and walking speed. Oral treatment with a combination of NAM/PN accelerates muscle repair in vivo by stimulating MuSCs and enhances recovery of muscle strength. In a human randomized placebo-controlled clinical trial using eccentric contraction-induced muscle regeneration in healthy volunteers, oral NAM/PN supplementation was well tolerated and stimulated the myogenic activity of MuSCs detected via increased number of MyoD and Myogenin positive cells in muscle biopsies during recovery. Collectively, our results establish NAM/PN as a promising nutritional intervention that stimulates MuSCs, enhances muscle repair, and alleviates muscle decline during aging, and opens new opportunities to enhance muscle recovery and manage regenerative capacity in muscle disorders through nutrition.

Most significant recent publications:
Trigonelline is an NAD+ precursor that improves muscle function during aging and is reduced in human sarcopenia. Membrez, Migliavacca , Christen,… JT Treebak,… Koopman, Lynch G, Sorrentino V and Feige JN. Nature Metabolism, 2024, 6(3):433-447.

Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice. Le Moal E, Liu Y, Collerette-Tremblay, , …, Feige JN, Auger-Messier M, Dumont NA, Bentzinger CF. Science Transl Med., 2024 20;16(739)

The mitochondrial calcium uniporter (MCU) promotes muscle energy metabolism and mobility by regulating mitochondrial redox state. Weiser A, Hermant A, …, Sorrentino V, Feige JN & De Marchi U.
Redox Biology, 2023, 64:102759

Evidence for inefficient contraction and abnormal mitochondrial activity in sarcopenia using magnetic resonance spectroscopy. Stephenson MC, Ho, …, Feige JN, Merchant RA, Tay SKH. J Cachexia Sarcopenia Muscle. 2023, 14(3):1482-1494

An Engineered Multicellular Stem Cell Niche for the 3D Derivation of Human Myogenic Progenitors from iPSCs. Mashinchian O, De Franceschi F,… G, Dumont NA, Lutolf MP, Feige JN*, Bentzinger CF*
EMBO J, 2022, 41(14):e110655. *: co-senior author

Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Migliavacca, E., Tay, S.K.H., Patel, H.P., …Karnani, N., Feige, JN. Nature Communications, 2019, 10(1), 5808

Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Signals Secretion from Fibro-Adipogenic Progenitors. Lukjanenko L, Karaz S, Stuelsatz P, …, Rudnicki MA, Bentzinger CF, Feige JN.
Cell Stem Cell, 2019, S1934-5909(18)30604-0.

The exerkine apelin reverses age-associated sarcopenia. Vinel C, Lukjanenko L,…, Feige JN, Vellas, Valet P, Dray C. Nature Medicine 2018, 24(9):1360-1371.

Loss of Fibronectin from the Aged Stem Cell Niche Affects the Regenerative Capacity of Skeletal Muscle in Mice. Lukjanenko L, Jung MJ, Hegde N, … , von Maltzahn J, Feige JN*, Bentzinger CF*. Nature Medicine 2016, 22(8):897-905. *: co-senior author