Knockout of MYOM1 in human cardiomyocytes leads to myocardial atrophy via impairing calcium homeostasis

Abstract

Myomesin‐1 (encoded by MYOM1 gene) is expressed in almost all cross‐striated muscles, whose family (together with myomesin‐2 and myomesin‐3) helps to cross‐link adjacent myosin to form the M‐line in myofibrils. However, little is known about its biological function, causal relationship and mechanisms underlying the MYOM1‐related myopathies (especially in the heart). Regrettably, there is no MYMO1 knockout model for its study so far. A better and further understanding of MYOM1 biology is urgently needed. Here, we used CRISPR/Cas9 gene‐editing technology to establish an MYOM1 knockout human embryonic stem cell line (MYOM1 −/− hESC), which was then differentiated into myomesin‐1 deficient cardiomyocytes (MYOM1 −/− hESC‐CMs) in vitro. We found that myomesin‐1 plays an important role in sarcomere assembly, contractility regulation and cardiomyocytes development. Moreover, myomesin‐1‐deficient hESC‐CMs can recapitulate myocardial atrophy phenotype in vitro. Based on this model, not only the biological function of MYOM1, but also the aetiology, pathogenesis, and potential treatments of myocardial atrophy caused by myomesin‐1 deficiency can be studied.

USP18 is an essential regulator of muscle cell differentiation and maturation

“…MYOM1 is essential for sarcomere stability and thereby crucial for contraction 58 . For instance, KO of MYOM1 in cardiomyocytes was found to impair calcium homeostasis together with reduced contraction 59 . Similarly, in USP18-depleted fused cells, calcium in ux was found to be impaired.…”

USP18 is an essential regulator of muscle cell differentiation and maturation

“…MYOM1 is essential for sarcomere stability and thereby crucial for contraction ( 48 ). For instance, KO of MYOM1 in cardiomyocytes was found to impair calcium homeostasis together with reduced contraction ( 49 ). Similarly, in USP18-depleted fused cells, calcium influx was found to be impaired.…”

Splicing factor Srsf5 deletion disrupts alternative splicing and causes noncompaction of ventricular myocardium

“…MYOM1 acts as a structural linker in the sarcomere M-line, connecting with muscle-type creatine kinase (MCK), Titin, and Obscurin ( Pernigo et al., 2017 ; Pinotsis et al., 2008 ). Myocardial atrophy has been observed in MYOM1-deficient embryonic stem cells, indicating that it plays an important role in the assembly of myofibrils ( Hang et al., 2021 ). EH-myomesin, the splice isoform of myomesin-1, generated by the inclusion of an elastic segment in the center of the molecule, is the main M-band component in the embryonic heart of vertebrates ( Agarkova et al., 2000 ).…”