Researchers here report on their investigation of the role of the long noncoding RNA CYTOR, involved in muscle function, and which declines in expression with age. As a class, long noncoding RNAs are comparatively poorly explored, and many, such as CYTOR, appear to participate in numerous critical cell functions, touching on structure, growth, and migration. Concretely, however, it seems that CYTOR is a potential target to improve muscle function in later life, and the work here shows that it can be upregulated to beneficial effect in mice via gene therapy strategies without immediately obvious side-effects.
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 CRISPR activation 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-minute 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.
In conclusion, the long noncoding RNA Cytor was found to be a regulator of fast-twitch myogenesis in aging. These findings may lead to the future development of interventions to improve myogenesis.