The role of the M-band myomesin proteins in muscle integrity and cardiac disease

Abstract

Transversal structural elements in cross-striated muscles, such as the M-band or the Z-disc, anchor and mechanically stabilize the contractile apparatus and its minimal unit—the sarcomere. The ability of proteins to target and interact with these structural sarcomeric elements is an inevitable necessity for the correct assembly and functionality of the myofibrillar apparatus. Specifically, the M-band is a well-recognized mechanical and signaling hub dealing with active forces during contraction, while impairment of its function leads to disease and death. Research on the M-band architecture is focusing on the assembly and interactions of the three major filamentous proteins in the region, mainly the three myomesin proteins including their embryonic heart (EH) isoform, titin and obscurin. These proteins form the basic filamentous network of the M-band, interacting with each other as also with additional proteins in the region that are involved in signaling, energetic or mechanosensitive processes. While myomesin-1, titin and obscurin are found in every muscle, the expression levels of myomesin-2 (also known as M-protein) and myomesin-3 are tissue specific: myomesin-2 is mainly expressed in the cardiac and fast skeletal muscles, while myomesin-3 is mainly expressed in intermediate muscles and specific regions of the cardiac muscle. Furthermore, EH-myomesin apart from its role during embryonic stages, is present in adults with specific cardiac diseases. The current work in structural, molecular, and cellular biology as well as in animal models, provides important details about the assembly of myomesin-1, obscurin and titin, the information however about the myomesin-2 and -3, such as their interactions, localization and structural details remain very limited. Remarkably, an increasing number of reports is linking all three myomesin proteins and particularly myomesin-2 to serious cardiovascular diseases suggesting that this protein family could be more important than originally thought. In this review we will focus on the myomesin protein family, the myomesin interactions and structural differences between isoforms and we will provide the most recent evidence why the structurally and biophysically unexplored myomesin-2 and myomesin-3 are emerging as hot targets for understanding muscle function and disease.

Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis

“…Utilizing the PhosphoPlus database, 48 none of the 15 sites have previously been assigned function, and among them, five sites were previously not identified using high or low throughput screening. The most upregulated site was R169 dimethylation on Y‐box‐binding protein 3 (YBX3), a repressor of immune cell function and maturation, 49 while R26 dimethylation of MYOM2, an M‐band structural protein responsible for sarcomere stability was the most downregulated 50 . Moreover, we observed significant upregulation of dimethylation of RNA binding protein—TAF15 (TATA‐box binding protein associated factor 15).…”

Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in Amyotrophic Lateral Sclerosis

“…The most upregulated site was R169 dimethylation on Y-box-binding protein 3 (YBX3), a repressor of immune cell function and maturation 49 . While R26 dimethylation of MYOM2, an M-band structural protein responsible for sarcomere stability was the most downregulated 50 . Moreover, we observed significant upregulation of dimethylation of RNA binding protein – TAF15 (TATA-box binding protein associated factor 15).…”

Loss of Cardiac Splicing Regulator RBM20 Is Associated With Early-Onset Atrial Fibrillation

“… 45 Myomesin 1, the protein product of MYOM1 , is part of the M-band and is important for sarcomere integrity. 46 Alternative splicing of MYOM1 is known to affect the stability of sarcomere M-bands, 47 and an up-regulation of a fetal isoform of myomesin 1 has been linked with dilated cardiomyopathy (DCM). 48 …”