Cellular heterogeneity is present on genomic, epigenomic, transcriptomic, proteomic and metabolomic levels. Single-cell approaches have revolutionized the detection of rare and subtle cellular subpopulations and are applicable to the majority of organs and tissues, including cardiac and skeletal muscles. Despite active research, many aspects of muscle heterogeneity remain unresolved. Examples for the latter, investigated in the current dissertation, are the evaluation of heterogeneity among cardiac muscle cells (CM) in basal vs. hypertrophic conditions, as well as juvenile vs. aged skeletal muscle stem cell (MuSCs) pool.In case of healthy adult cardiomyocytes wide ranging homogeneity was found with only minor transcriptional differences between cells of different nuclearity. When homeostasis was disturbed by traverse aortic constriction, which led to cardiac hypertrophy, a notable transcriptional heterogeneity among cardiomyocytes developed. Furthermore, cardiomyocytes located in poorly vascularized zones of the hypertrophic myocardium showed transcriptional signatures characteristic for hypoxic responses. In contrast to cardiomyocytes, strong cellular heterogeneity was found among quiescent MuSCs already at early age (2 month), which further changed with ageing (24 month). In particular, a subpopulation of quiescent MuSCs, defined by expression of the Gal gene, decreased, while a subpopulation expressing the Anxa3 gene emerged with age. Based on these findings, lack of Galanin and the induction of Annexin A3 were hypothesized to be of functional significance in the context of age- related reduction of muscle regeneration capacity. Systemic supplementation of Galanin peptide was applied to aged mice to restore juvenile levels of the neuropeptide. Intriguingly, application of Galanin partially rejuvenated the transcriptional profile of aged quiescent MuSCs. On the other hand, overexpression of Anxa3 gene in quiescent MuSCs abolished muscle regeneration and induced extensive muscle fibrosis in young mice, resembling conditions in aged muscles. Thus, Gal and Anxa3 are potential crucial factors, important for muscle regeneration in ageing animals.In conclusion, this work shows that cellular heterogeneity is not detectable among cardiomyocytes of different nuclearity, but appears when cardiomyocytes adapt to hypoxic conditions. Heterogeneity is, however, occurring in MuSCs upon ageing. The work presented in this thesis lays the groundwork to investigate whether the observed transcriptional and epigenetic heterogeneity is of functional relevance for organ homeostasis and pathological reactions in disease.
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