Machaj, G. | bioRxiv Science

bioRxiv2026

miR-378a Controls Cardiomyocyte Metabolism and Angiogenic Signaling

AimsWhile the muscle-enriched microRNA-378a (miR-378a) has been implicated in cardiac hypertrophy and stress responses, its role in maintaining cardiomyocyte metabolic homeostasis, mitochondrial function, and angiogenic paracrine signaling under physiological and post-injury conditions remains unclear. This study addresses these gaps by examining the molecular and functional consequences of miR-378a deficiency in murine heart and human cardiomyocytes. Methods and ResultsCardiac structure and function were analyzed in miR-378a-deficient (miR-378a-/-) and wild-type (miR-378a+/+) mice at 12 weeks and 17 months of age, revealing that miR-378a loss promoted myocardial fibrosis, altered IGF1R-AKT signaling, and impaired cardiac performance, with age-dependent effects. Integrated transcriptomic and proteomic analyses in miR-378a-/- and control mice, as well as in human iPSC-derived cardiomyocytes (hiPSC-CM) of both genotypes, revealed deregulated pathways related to translation, metabolism, and cardiomyopathy-associated signaling. In hiPSC-CM, miR-378a knockout (KO) impaired mitochondrial respiration, disrupted mitochondrial morphology, and reduced mitochondrial DNA content, accompanied by altered mitophagy and biogenesis. KO cells also showed increased glucose uptake but reduced glycogen storage, accompanied by changes in key metabolic regulators, and displayed diminished angiogenic potential. Finally, hiPSC-CM overexpressing miR-378a were delivered in a mouse model of acute myocardial infarction, but overexpression did not further enhance their therapeutic effect. ConclusionsThis study broadens our understanding of miR-378as physiological role in murine hearts and human cardiomyocytes, demonstrating its impact on contractility, mitochondrial integrity, glucose metabolism, and angiogenic paracrine signaling. However, overexpression of miR-378a in hiPSC-CM offers limited additional benefit in cell therapy for acute myocardial infarction.

cell biology↗

bioRxiv2022

Reduction of embryonic E93 expression as a key factor for the evolution of insect metamorphosis

The early embryo of the cockroach Blattella germanica exhibits high E93 expression. In general, E93 triggers adult morphogenesis during postembryonic development, but in the cockroach E93 is also crucial in early embryogenesis. Moreover, the embryonic levels of E93 expression are high in hemimetabolan insects, while in holometabolans they are very low. They are also low in Thysanoptera and in Hemiptera Sternorrhyncha with postembryonic quiescent stages, as well as in Odonata, the nymph of which is very different from the adult. In ametabolans, such as the Zygentoma Thermobia domestica, E93 expression levels are very high in the early embryo, whereas during postembryonic development they are medium and relatively constant. Given that embryogenesis of hemimetabolans yields an adultiform nymph, we speculate that E93 plays some sort of adult triggering role in the embryo of these species. We conjecture that the reduction of E93 transcript levels in the embryo has been instrumental in the evolution of insect metamorphosis. The suppression of E93 expression during the nymphal period, and its concentration in the preadult stage, is consubstantial with the emergence of hemimetaboly. As such, attenuation of E93 expression in the embryo could have resulted in a larval genetic program and the emergence of holometaboly. Independent decreases of E93 expression in the embryo of Odonata, Thysanoptera, and different groups of Hemiptera Sternorrhyncha would have allowed the development of modified juvenile stages adapted to specific ecophysiological conditions.

developmental biology↗