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However, human in vivo studies offer limited insights into the underlying mechanisms of these potential deleterious effects. This study investigated exercise-induced cardiac troponin release, cardiac fatigue, and its potential mechanisms in a versatile in vitro Engineered Heart Tissue (EHT) model. EHTs were subjected to exercise-like electrical pulse stimulation (EL-EPS) at 2.5\u00a0Hz (150\u00a0bpm) for 2 or 4\u00a0h and compared to non-stimulated controls and doxorubicin (DOX)-exposed tissues. High-sensitive cardiac troponin T (hs-cTnT), lactate dehydrogenase (LDH), and cardiomyocyte contractile function were measured at baseline, immediately after EL-EPS, and after 20\u00a0h of recovery. Cell death was quantified by nuclear and mitochondrial DNA concentrations and tissue integrity was assessed using microscopy following exposure. Following 2 and 4\u00a0h of EL-EPS, and after DOX exposure, we found increased hs-cTnT and LDH levels and reduced contractile function compared to control. After recovery, contractile function remained impaired after 4\u00a0h EL-EPS and DOX exposure, whereas the effects were abolished after recovery for the 2\u00a0h EL-EPS group. Elevated nuclear and mitochondrial DNA release was found following DOX, but not after 2 and 4\u00a0h EL-EPS. Finally, EL-EPS was associated with the formation of actin aggregates. EL-EPS induced dose-dependent increases in hs-cTnT and LDH concentrations in conjugation with signs of cardiac fatigue, but without elevated markers of permanent cell death (i.e., mitochondrial\/nuclear DNA). These findings suggest that exercise-induced elevations of cardiac biomarker concentrations are indicative of reversible cardiac injury.<\/jats:p>","DOI":"10.1007\/s00395-026-01182-9","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T18:13:00Z","timestamp":1777572780000},"page":"725-737","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dose-dependent effects and mechanisms of exercise-like stimulation on cardiac injury and contractile function: outcomes of the MICRO-ATHLETE study"],"prefix":"10.1007","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2312-0414","authenticated-orcid":false,"given":"Tom T. 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