Molecular regulation of myocyte fusion

Abstract

Myocyte fusion is a pivotal process in the development and regeneration of skeletal muscle. Failure during fusion can lead to a range of developmental as well as pathological consequences. This review aims to comprehensively explore the intricate processes underlying myocyte fusion, from the molecular to tissue scale. We shed light on key players, such as the muscle-specific fusogens - Myomaker and Myomixer, in addition to some lesser studied molecules contributing to myocyte fusion. Conserved across vertebrates, Myomaker and Myomixer play a crucial role in driving the merger of plasma membranes of fusing myocytes, ensuring the formation of functional muscle syncytia. Our multiscale approach also delves into broader cell and tissue dynamics that orchestrate the timing and positioning of fusion events. In addition, we explore the relevance of muscle fusogens to human health and disease. Mutations in fusogen genes have been linked to congenital myopathies, providing unique insights into the molecular basis of muscle diseases. We conclude with a discussion on potential therapeutic avenues that may emerge from manipulating the myocyte fusion process to remediate skeletal muscle disorders.

Keywords: Carey-Fineman-Ziter syndrome; Fusogen; Myocyte fusion; Myogenesis; Myomaker; Myomixer; Myopathies.

Figure 1.

A) General process myocyte fusion highlighting critical molecules. B) Schematic showing interaction between cytoskeletal proteins in myocytes and ECM molecules thought to contribute to myoblast fusion potentially by enhancing fusogen engagement.

Figure 2.

General topology of membrane fusogens.

Figure 3.

A) Fusion events are coordinated on a tissue scale. Cross-sectional view through the developing zebrafish myotome. Left: early somite stage, just after segmentation from the presomitic mesoderm. Slow fibers are specified. Middle: Subsequently, fusion events (magenta) begin amongst the fast fiber population, with a bias towards the medial myotome surface. Right: The slow fibers (cyan) migrate to the lateral surface, which appear to coordinate the fast myocyte fusion events. B) Corresponding images to A from a 24 - 32 hour zebrafish embryo, showing the formation of muscle fibers (from a dorsal-ventral view). Images courtesy of Mario Mendieta-Serrano. C) Pictorial graph demonstrating fusion events at a local scale occurring in an uncoordinated manner.

Figure 4.

Overview of phenotypes associated with Carey-Fineman-Ziter syndromes.