Evolution of a chordate-specific mechanism for myoblast fusion

Abstract

The size of an animal is determined by the size of its musculoskeletal system. Myoblast fusion is an innovative mechanism that allows for multinucleated muscle fibers to compound the size and strength of individual mononucleated cells. However, the evolutionary history of the control mechanism underlying this important process is currently unknown. The phylum Chordata hosts closely related groups that span distinct myoblast fusion states: no fusion in cephalochordates, restricted fusion and multinucleation in tunicates, and extensive, obligatory fusion in vertebrates. To elucidate how these differences may have evolved, we studied the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here we report that Myomaker likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while Myomixer appears to have evolved de novo in early vertebrates. Functional tests revealed an unexpectedly complex evolutionary history of myoblast fusion in chordates. A pre-vertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Thus, our findings reveal the evolutionary origins of chordate-specific fusogens and illustrate how new genes can shape the emergence of novel morphogenetic traits and mechanisms.

Ca2+ as a coordinator of skeletal muscle differentiation, fusion and contraction

“…A recent study has suggested that MYMK and MYMX have coevolved in the vertebrates [ 119 ]. These observations indicate that MYMK and MYMX evolved together for myoblast fusion, parallel to the emergence of sarcomeric muscle and EC coupling in this lineage [ 120 ].…”

Microproteins in skeletal muscle: hidden keys in muscle physiology

“…No Myomixer orthologue was found in non-vertebrate chordate groups, indicating that Myomixer is a vertebrate-specific gene with myoblast fusion functions, conserved from lampreys to humans. 92 In response to muscle injury (CTX), Myomixer expression is immediately increased and is essential for satellite cell fusion, demonstrating an important function during the process of muscle regeneration. Besides, Myomixer-knockout mice embryos have lack of skeletal muscle and absence of multinucleated myofibres, which Myomixer being required for skeletal muscle development in vivo and in vitro.…”

“…Although lamprey Myomixer is a 583‐aa protein and exhibits sequence divergence, it is capable to replace human Myomixer and promote myoblast fusion. No Myomixer orthologue was found in non‐vertebrate chordate groups, indicating that Myomixer is a vertebrate‐specific gene with myoblast fusion functions, conserved from lampreys to humans 92 …”