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The associated pathology is characterized by a loss of cardiomyocytes that leads, eventually, to heart failure. In this context, several cardiac regenerative strategies have been developed, but they still lack clinical effectiveness. The mammalian neonatal heart is capable of substantial regeneration following injury, but this capacity is lost at postnatal stages when cardiomyocytes become terminally differentiated and transit to the fetal metabolic switch. Cardiomyocytes are metabolically versatile cells capable of using an array of fuel sources, and the metabolism of cardiomyocytes suffers extended reprogramming after injury. Apart from energetic sources, metabolites are emerging regulators of epigenetic programs driving cell pluripotency and differentiation. Thus, understanding the metabolic determinants that regulate cardiomyocyte maturation and function is key for unlocking future metabolic interventions for cardiac regeneration. In this review, we will discuss the emerging role of metabolism and nutrient signaling in cardiomyocyte function and repair, as well as whether exploiting this axis could potentiate current cellular regenerative strategies for the mammalian heart.<\/jats:p>","DOI":"10.3390\/metabo12060500","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T09:24:29Z","timestamp":1653989069000},"page":"500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Metabolic Determinants in Cardiomyocyte Function and Heart Regenerative Strategies"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6967-3073","authenticated-orcid":false,"given":"Magda","family":"Correia","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Francisco","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Rita","family":"da Silva Ferreira","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6872-4051","authenticated-orcid":false,"given":"Rita","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Associated Laboratory for Green Chemistry\u2014LAQV, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6407-3466","authenticated-orcid":false,"given":"Bruno","family":"Bernardes de Jesus","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9652-1382","authenticated-orcid":false,"given":"Sandrina","family":"N\u00f3brega-Pereira","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease and Stroke Statistics 2021 Update","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nature10147","article-title":"Heart regeneration","volume":"473","author":"Laflamme","year":"2011","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41569-018-0036-6","article-title":"Therapeutic approaches for cardiac regeneration and repair","volume":"15","author":"Hashimoto","year":"2018","journal-title":"Nat. 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