Key result
HOIL-1L deficiency disrupts cell cycles, alters morphology, and upregulates fibrogenic SerpinE2 in cardiomyocytes and myotubes.
Why the study?
HOIL-1L deficiency was recently identified as a cause of myopathy and dilated cardiomyopathy, but the underlying mechanisms remained unclear.
HOIL-1L deficiency impairs myotube and cardiomyocyte maturation and promotes fibrogenesis, elucidating potential mechanisms for HOIL-1L-associated myopathy and dilated cardiomyopathy.
HOIL-1L deficiency may impair cardiomyocyte maturation; hypothesis-generating for myopathy mechanisms, requires validation before clinical relevance.
HOIL-1L deficiency was recently reported to be one of the causes of myopathy and dilated cardiomyopathy (DCM). However, the mechanisms by which myopathy and DCM develop have not been clearly elucidated. Here, we sought to elucidate these mechanisms using the murine myoblast cell line C2C12 and disease-specific human induced pluripotent stem cells (hiPSCs). Myotubes were differentiated from control and HOIL-1L-KO C2C12 cells. Cardiomyocytes (CMs) were differentiated from control and patient-derived hiPSCs. We investigated the impact of HOIL-1L on differentiation of myotubes and CMs. Myotubes differentiated from HOIL-1L-KO C2C12 cells exhibited deteriorated differentiation and mitotic cell accumulation. CMs differentiaed from patient-derived hiPSCs had an abnormal morphology with a larger size and were excessively multinucleated compared with CMs differentiaed from control hiPSCs. Further analysis of hiPSC- derived CMs showed that HOIL-1L deficiency caused cell cycle alteration and mitotic cell accumulation. These results were supported by RNA sequencing of C2C12 cell-derived myotubes. In addition, SerpinE2 , a cardiac fibrogenesis gene, was significantly upregulated in CMs differentiaed from patient-derived hiPSCs. These results demonstrate that abnormal cell maturation and fibrosis possibly contribute to the development of DCM and myopathy. In conclusion, HOIL-1L is an important intrinsic regulator of cell cycle-related myotube and CM maturation and cell proliferation.
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Akagi et al. (2023) studied Myopathy and dilated cardiomyopathy. HOIL-1L deficiency vs. Control cells was evaluated on Impact of HOIL-1L on differentiation of myotubes and cardiomyocytes. HOIL-1L deficiency caused cell cycle alteration, mitotic cell accumulation, abnormal morphology, and upregulation of the fibrogenesis gene SerpinE2 in cardiomyocytes and myotubes.
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