Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures

Abstract

Cardiac muscle is equipped with intricate intrinsic mechanisms to regulate adaptive remodeling. Recent and extensive experimental findings powered by novel strategies for screening protein-protein interactions, improved imaging technologies, and versatile transgenic mouse methodologies reveal that Z disks and titin filaments possess unexpectedly complicated sensory and modulatory mechanisms for signal reception and transduction. These mechanisms employ molecules such as muscle-enriched LIM domain proteins, PDZ-LIM domain proteins, myozenin gene family members, titin-associated ankyrin repeat family proteins, and muscle-specific ring finger proteins, which have been identified as potential molecular sensor components. Moreover, classic transmembrane signaling processes, including mitogen-activated kinase, protein kinase C, and calcium signaling, also involve novel interactions with the Z disk/titin network. This compartmentalization of signaling complexes permits alteration of receptor-dependent transcriptional regulation by direct sensing of intrinsic stress. Newly identified mechanical stress sensors are not limited to Z-disk region and to I-band and M-band regions of titin but are also embedded in muscle-specific membrane systems such as the costamere, intercalated disks, and caveolae-like microdomains. This review summarizes current knowledge of this rapidly developing area with focus on how the heart adjusts physiological remodeling process to meet with mechanical demands and how this process fails in cardiac pathologies.

Fig. 1

Mechanical stress sensing and subcellular domains in cardiomyocytes. The simple classical view of cardiac stress signaling (A) has been evolving. Mechanical sensor functions have been linked to distinctive subcellular domains (B).

Fig. 2

Cardiac Z disk/titin cytoskeletal structure-associated proteins. An increasing number of molecules have been identified on or in the vicinity of cardiac Z disk/titin cytoskeleton. Many of these proteins have been linked to intrinsic mechanical sensor sensor/signal modulator functions. See text for details. MYOZ2, myozenin 2 (carsarin 1); Cn, calcineurin; PDZ-3LIM, one-PDZ and three-LIM domain protein; PDZ-1LIM, one-PDZ and one-LIM domain protein; MLP/CRP3, muscle-specific LIM protein/cysteine-rich protein 3; FHL2, four-and-a-half LIM protein 2; MAPRs, muscle ankyrin repeat proteins; MURFs, muscle-specific ring-finger proteins.

Fig. 3

Z disk/I band titin associated signal cascades. Several nodal molecules of transmembrane signaling have been mapped on Z disks and I band titin. Mitogen-activated protein (MAP) kinase cascade interact with I-band titin through ERK2-FHL2 association. Calcium signal activates calcineurin (Cn) and subsequently nuclear factor of activated T cells (NFAT). The interaction of Cn with two distinctive Z disk proteins has been revealed (MYZO2 and MLP/CRP3). A subset of PKC isotypes localize at Z disk or its vicinity and PDZ-3LIM proteins (enigma, enigma homolog, and LIM domain-binding factor 3) may be critical for their sequestration.

Fig. 4

Sarcomere protein turnover and Z disk/M-band-associated ubiquitin (Ub) ligase complexes. Ubiqutination-dependent protein turnover may critically regulate turnover of cardiac proteins. Selective localizations of E3 ubiquitin ligase complex components have been identified: MURFs at M-band titin and atrogin-1 at Z disks. In addition to their direct interaction with sarocomere proteins, M-band MURF may regulate the SRF transcriptional factor, and atrogin-1 binds and induces degradation of Cn at Z disk. Collectively, sarcomere-associated ubiquitine ligase components may serve as critical regulators of both cardiac protein synthesis and degradation.

Fig. 5

Sarcolemmal actin assembly and nuclear signaling. Recent studies have revealed that cytoplasmic actin assembly/disassembly may regulate transcriptional factors. The rho GTPase is a nodal molecule of this pathway and has been linked to various sarcolemmal activators (G protein coupling receptors, GPCR; tyrosine-kinase receptors, TyR; adhesion plaque complexes; and the caveolae-like structure). Cytoplasmic actin assembly has been found to regulate SRF transcriptional activities through G-actin association with megakaryotic acute leukemia (MAL)/myocardin-related transcriptional factors (MRTF) proteins. STARS (striated muscle activator of rho signaling) also regulates actin disassembly.