Structural and signaling proteins in the Z-disk and their role in cardiomyopathies

Abstract

The sarcomere is the smallest functional unit of muscle contraction. It is delineated by a protein-rich structure known as the Z-disk, alternating with M-bands. The Z-disk anchors the actin-rich thin filaments and plays a crucial role in maintaining the mechanical stability of the cardiac muscle. A multitude of proteins interact with each other at the Z-disk and they regulate the mechanical properties of the thin filaments. Over the past 2 decades, the role of the Z-disk in cardiac muscle contraction has been assessed widely, however, the impact of genetic variants in Z-disk proteins has still not been fully elucidated. This review discusses the various Z-disk proteins (alpha-actinin, filamin C, titin, muscle LIM protein, telethonin, myopalladin, nebulette, and nexilin) and Z-disk-associated proteins (desmin, and obscurin) and their role in cardiac structural stability and intracellular signaling. This review further explores how genetic variants of Z-disk proteins are linked to inherited cardiac conditions termed cardiomyopathies.

Broad therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy

“…R502W hearts also express sarcomeric protein isoforms typical of the fetal gene program that is common in HCM (reduced Myh6 / Myh7 ratio and increased Acta1 ) 28,33 ( Supplementary Figure S8C ). We also detected alteration of expression other sarcomere components, including upregulation of the Z-disc-associated Csrp3 , Flnc and Des , which play roles in mechanosensing and structural integration with the non-sarcomeric cytoskeleton 34 ( Supplementary Figure S8D ). Regarding metabolic genes, the expression profile of R502W myocardium includes downregulation of Cpt2 , Acadvl , Hadha, Hadhb, Eci2 and Ech1 , involved in fatty acid oxidation, and Pcx , Cs and Sucla2 , which participate in the tricarboxylic acid cycle ( Supplementary Figure S8E,F ).…”

Pathophysiological mechanisms of cardiomyopathies induced by desmin gene variants located in the C‐Terminus of segment 2B

“…The desmin network plays a key role in structural integrity, mechano-transduction and mechano-sensation of muscle cells. It traverses the cardiomyocyte and forms interactions along the way from laterally linking and aligning myofibrils at the Z-disks (Bär et al, 2004;Granger & Lazarides, 1979;Huang et al, 2002;Noureddine & Gehmlich, 2023) to connecting the contractile apparatus to the nucleus, mitochondria, T-tubules, and the sarcolemma at the level of costamers (Bär et al, 2004;Brodehl et al, 2018;Dalakas et al, 2000;Lazarides, 1978;Spörrer et al, 2022). Desmin interacts with the desmosomes of the intercalated disks through desmoplakin which helps dampen the generated forces and tension from every cardiac contraction (Dalakas et al, 2000;Lapouge et al, 2006).…”

An optimized approach to study nanoscale sarcomere structure utilizing super-resolution microscopy with nanobodies

“…For example, numerous proteins localize within the Z-disc, a 30-140nm lateral space depending on the muscle and species [5,57]. Even within this nanoscale domain, there is a region-specific pattern to the localization of specific proteins [17,[58][59][60][61][62][63][64]. Commonly used confocal microscopy cannot resolve region specific localization of Z-disc proteins, resulting in the often-vague "Z-disc localizing" characterization of proteins.…”