title: A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia.
abstract: Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motoneuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Alice
authors.initials: A
authors.lastname: Pannérec
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Margherita
authors.initials: M
authors.lastname: Springer
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.affiliation: School of Healthcare Science, Manchester Metropolitan University, Manchester, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Ireland
authors.affiliation: School of Healthcare Science, Manchester Metropolitan University, Manchester, UK.
authors.forename: Mathew
authors.initials: M
authors.lastname: Piasecki
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Karaz
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacot
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Métairon
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: Danenberg
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Raymond
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Descombes
authors.affiliation: School of Healthcare Science, Manchester Metropolitan University, Manchester, UK.
authors.forename: Jamie S
authors.initials: JS
authors.lastname: McPhee
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Jerome N
authors.initials: JN
authors.lastname: Feige
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D000818:Animals; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D055948:Sarcopenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome; D055815:Young Adult
keywords: neuromuscular junction; physical frailty; sarcopenia; skeletal muscle