MICAL2 is essential for myogenic lineage commitment

Nefele Giarratana,Domiziana Costamagna,Rik Gijsbers,Flavio Ronzoni,Roberto Piciotti,Paolo Carai,Stefania Fulle,Maurilio Sampaolesi,Ivana Barravecchia,Filippo Conti,Tim Vervliet,Geert Bultynck,Debora Angeloni,Yvan Torrente,Robin Duelen,Rita La Rovere

doi:10.1038/s41419-020-02886-z

Abstract

Contractile myofiber units are mainly composed of thick myosin and thin actin (F-actin) filaments. F-Actin interacts with Microtubule Associated Monooxygenase, Calponin And LIM Domain Containing 2 (MICAL2). Indeed, MICAL2 modifies actin subunits and promotes actin filament turnover by severing them and preventing repolymerization. In this study, we found that MICAL2 increases during myogenic differentiation of adult and pluripotent stem cells (PSCs) towards skeletal, smooth and cardiac muscle cells and localizes in the nucleus of acute and chronic regenerating muscle fibers. In vivo delivery of Cas9–Mical2 guide RNA complexes results in muscle actin defects and demonstrates that MICAL2 is essential for skeletal muscle homeostasis and functionality. Conversely, MICAL2 upregulation shows a positive impact on skeletal and cardiac muscle commitments. Taken together these data demonstrate that modulations of MICAL2 have an impact on muscle filament dynamics and its fine-tuned balance is essential for the regeneration of muscle tissues.

Highlights

Muscle tissue represents 40% of human body mass and provides locomotion, posture support and it is required for breathing
Further proof of MICAL2 importance in myogenesis has been evaluated in loss and gain of function studies of these two cellular types (Supplementary Figs. 1–3)
A higher number of cells is gathered in the S phase of MICAL2 silenced cells compared to lipofectamine treated cells (22% vs 15% and ~21% vs ~12% at 24 h and 36 h, respectively), meaning that cells lacking MICAL2 were more prone to proliferation (Supplementary Fig. 1b)

Summary

Introduction

Muscle tissue represents 40% of human body mass and provides locomotion, posture support and it is required for breathing. Once the muscle is mature, a subpopulation of Pax7+ cells becomes quiescent as satellite cells (SCs) and muscle renewal and regeneration rely on the activated SCs that have the potential to fuse and form new fibers, as well as maintaining the stem cell niche[2,3,4]. This process occurs in adult tissue when muscles are damaged[5] to restore the damaged contractile myofiber units[6].

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