A1 Refereed original research article in a scientific journal
The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging
Authors: Wohlwend Martin, Laurila Pirkka-Pekka, William Kristine, Romani Mario, Lima Tanes, Pattawaran Pattamaprapanont, Benegiamo Georgia, Salonen Minna, Schneider Bernard L, Lahti Jari, Eriksson Johan G, Barres Romain, Wisløff Ulrik, Moreira José BN, Auwerx Johan
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Publication year: 2021
Journal:Science Translational Medicine
Journal name in sourceSCIENCE TRANSLATIONAL MEDICINE
Journal acronym: SCI TRANSL MED
Article number: ARTN eabc7367
Volume: 13
Issue: 623
Number of pages: 13
ISSN: 1946-6234
eISSN: 1946-6242
DOI: https://doi.org/10.1126/scitranslmed.abc7367
Web address : https://www.science.org/doi/10.1126/scitranslmed.abc7367
Skeletal muscle displays remarkable plasticity upon exercise and is also one of the organs most affected by aging. Despite robust evidence that aging is associated with loss of fast-twitch (type II) muscle fibers, the underlying mechanisms remain to be elucidated. Here, we identified an exercise-induced long noncoding RNA, CYTOR, whose exercise responsiveness was conserved in human and rodents. Cytor overexpression in mouse myogenic progenitor cells enhanced myogenic differentiation by promoting fast-twitch cell fate, whereas Cytor knockdown deteriorated expression of mature type II myotubes. Skeletal muscle Cytor expression was reduced upon mouse aging, and Cytor expression in young mice was required to maintain proper muscle morphology and function. In aged mice, rescuing endogenous Cytor expression using adeno-associated virus serotype 9 delivery of CRISPRa reversed the age-related decrease in type II fibers and improved muscle mass and function. In humans, CYTOR expression correlated with type II isoform expression and was decreased in aged myoblasts. Increased CYTOR expression, mediated by a causal cis-expression quantitative trait locus located within a CYTOR skeletal muscle enhancer element, was associated with improved 6-min walk performance in aged individuals from the Helsinki Birth Cohort Study. Direct CYTOR overexpression using CRISPRa in aged human donor myoblasts enhanced expression of type II myosin isoforms. Mechanistically, Cytor reduced chromatin accessibility and occupancy at binding motifs of the transcription factor Tead1 by binding, and hence sequestering, Tead1. In conclusion, the long noncoding RNA Cytor was found to be a regulator of fast-twitch myogenesis in aging.
