The exercise-induced long noncoding RNA <i>CYTOR</i> promotes fast-twitch myogenesis in aging

Abstract

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, <i>CYTOR</i>, whose exercise responsiveness was conserved in human and rodents. <i>Cytor</i> overexpression in mouse myogenic progenitor cells enhanced myogenic differentiation by promoting fast-twitch cell fate, whereas <i>Cytor</i> knockdown deteriorated expression of mature type II myotubes. Skeletal muscle <i>Cytor</i> expression was reduced upon mouse aging, and <i>Cytor</i> expression in young mice was required to maintain proper muscle morphology and function. In aged mice, rescuing endogenous <i>Cytor</i> 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, <i>CYTOR</i> expression correlated with type II isoform expression and was decreased in aged myoblasts. Increased <i>CYTOR</i> expression, mediated by a causal cis–expression quantitative trait locus located within a <i>CYTOR</i> skeletal muscle enhancer element, was associated with improved 6-min walk performance in aged individuals from the Helsinki Birth Cohort Study. Direct <i>CYTOR</i> overexpression using CRISPRa in aged human donor myoblasts enhanced expression of type II myosin isoforms. Mechanistically, <i>Cytor</i> reduced chromatin accessibility and occupancy at binding motifs of the transcription factor <i>Tead1</i> by binding, and hence sequestering, <i>Tead1</i>. In conclusion, the long noncoding RNA <i>Cytor</i> was found to be a regulator of fast-twitch myogenesis in aging.