The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging
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The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging. / Wohlwend, Martin; Laurila, Pirkka-Pekka; William, Kristine; Romani, Mario; Lima, Tanes; Pattawaran, Pattamaprapanont; Benegiamo, Giorgia; Salonen, Minna; Schneider, Bernard L.; Lahti, Jari; Eriksson, Johan G.; Barres, Romain; Wisloff, Ulrik; Moreira, Jose B. N.; Auwerx, Johan.
In: Science Translational Medicine, Vol. 13, No. 623, eabc7367, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging
AU - Wohlwend, Martin
AU - Laurila, Pirkka-Pekka
AU - William, Kristine
AU - Romani, Mario
AU - Lima, Tanes
AU - Pattawaran, Pattamaprapanont
AU - Benegiamo, Giorgia
AU - Salonen, Minna
AU - Schneider, Bernard L.
AU - Lahti, Jari
AU - Eriksson, Johan G.
AU - Barres, Romain
AU - Wisloff, Ulrik
AU - Moreira, Jose B. N.
AU - Auwerx, Johan
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.abc7367
DO - 10.1126/scitranslmed.abc7367
M3 - Journal article
C2 - 34878822
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 623
M1 - eabc7367
ER -
ID: 286998488