Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia include inflammation, muscle stem cell depletion, mitochondrial dysfunction and loss of motor neurons, but whether there are key drivers of sarcopenia is not yet known.

To gain deeper insights into age-related sarcopenia, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, old and sarcopenic subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed novel changes in gene expression that occur with age and sarcopenia in multiple cell types comprising mature skeletal muscle.

To validate our findings, we performed digital spatial profiling to confirm key genes identified in our bulk and single nuclei gene expression studies on fixed human muscle tissue. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related sarcopenia.

Dr. Simon Melov Professor, Buck Institute for Research on Aging

Dr. Simon have a long interest in the functional decline in aging, coupled with expertise in pre-clinical phenotyping, and exploring gene regulation in multiple model systems of aging. He have investigated gene expression in mitochondrial dysfunction, exercise, and aging in human skeletal muscle, and published numerous studies in this context. Dr. Simon have also worked with various mouse models of aging and age-related disease for more than 20 years. He has applied my diverse aging expertise in multiple partnerships, which have resulted in many impactful publications. Over the last few years, Dr. Simon formed multiple cores designed to help develop and drive research at the Buck Institute; the Mouse Phenotyping Core, and the Single Cell Core. He has been actively developing and applying these technologies for the last few years in multiple collaborations throughout the institute.