Key result
Targeted ERK activation via BRAF-V600E expression in neonatal rat cardiomyocytes induced sustained cell cycling, a shift to glycolytic metabolism, loss of contractile function, and increased tissue stiffness.
Why the study?
Because ERBB2 regulates multiple pathways beyond ERK, it remained unclear whether ERK activation alone is sufficient to drive cardiomyocyte proliferation.
Direct ERK activation via caBRAF modulates cardiomyocyte cycling, induces a shift to glycolytic metabolism, and alters functional maturation, highlighting a potential pathway for cardiac regenerative therapies.
Mitogens capable of promoting cardiomyocyte proliferation represent important targets for functional heart regeneration following myocardial infarction. We previously described an ERK-dependent pro-proliferative tissue phenotype following overexpression of constitutively-active (ca) human ERBB2 in both neonatal rat ventricular myocytes (NRVMs) and human iPSC-derived cardiomyocytes (hiPSC-CMs). Since ERBB2 canonically regulates multiple other pathways in addition to ERK, it is unclear whether ERK activation alone can drive CM proliferation. Here, we activated ERK in a targeted fashion by CM-specific lentiviral expression of a constitutively active mutant of BRAF, BRAF-V600E (caBRAF), in cultured NRVMs and examined the effects on engineered NRVM tissue proliferation, morphology, and function. caBRAF expression induced ERK activation, tissue growth, loss of contractile function, and increased tissue stiffness, all of which were sustained for at least 4 weeks in vitro . From bulk RNA-sequencing analysis of engineered tissues, we found that caBRAF had broad transcriptomic effects on CMs and induced a shift to glycolytic metabolism. Together, this work shows that direct ERK activation is sufficient to modulate CM cycling and functional maturation in a cell-autonomous fashion and could offer a potential target for cardiac regenerative therapies.
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Strash et al. (2022) studied Myocardial Infarction / Heart Regeneration. BRAF-V600E (caBRAF) lentiviral expression vs. Control Lentivirus (MHCK7-mCherry) was evaluated on Cell cycling, morphological changes, and contractile function in engineered cardiac tissues. Targeted ERK activation via BRAF-V600E expression in neonatal rat cardiomyocytes induced sustained cell cycling, a shift to glycolytic metabolism, loss of contractile function, and increased tissue stiffness.
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