Abstract
Muscle specific signaling has been shown to originate from myofilaments and their associated cellular structures, including the sarcomeres, costameres or the cardiac intercalated disc. Two signaling hubs that play important biomechanical roles for cardiac and/or skeletal muscle physiology are the N2B and N2A regions in the giant protein titin. Prominent proteins associated with these regions in titin are chaperones Hsp90 and αB-crystallin, members of the four-and-a-half LIM (FHL) and muscle ankyrin repeat protein (Ankrd) families, as well as thin filament-associated proteins, such as myopalladin. This review highlights biological roles and properties of the titin N2B and N2A regions in health and disease. Special emphasis is placed on functions of Ankrd and FHL proteins as mechanosensors that modulate muscle-specific signaling and muscle growth. This region of the sarcomere also emerged as a hotspot for the modulation of passive muscle mechanics through altered titin phosphorylation and splicing, as well as tethering mechanisms that link titin to the thin filament system.
Highlights
The myofilaments of cross-striated muscle cells provide mechanical power for the contraction of the heart or the movement of the skeletal muscles
The machinery that drives the power development serves additional functions: as a mechanosensory unit that provides constant feedback on the current power requirements, as a signaling node that integrates the input of muscle specific components and sensors with common cellular signaling pathways to modulate the muscle gene program and as finely tuned regulators of active and passive force development and tension
Many of these functions emanate from and are mediated by three filament systems: actin, myosin and titin filaments, as well as an intricate system of accessory proteins and cellular structures, such as the intercalated discs or costameres
Summary
The myofilaments of cross-striated muscle cells provide mechanical power for the contraction of the heart or the movement of the skeletal muscles. These mutations are commonly associated with a widely variable clinical presentation in affected patients This variability may relate to the multifaceted roles of FHL1 isoforms in striated muscles, including their ability to function as molecular adaptor and scaffolding proteins within the sarcomere in conjunction with their regulation of cell signaling within the cytosol and gene transcription within the nucleus. Studies performed in FHL1 knockout mice have shown that FHL1 is part of a biomechanical stress sensor complex that scaffolds mitogen-activated protein kinase (Mapk) components (Erk, Raf, Mek2) to the sarcomeric titin N2Bus spring element, regulating diastolic function and cardiac stress responses through N2Bus phosphorylation and Mapk signaling (Raskin et al 2012; Sheikh et al 2008). Only cre-positive wildtype and double knockout animals are counted
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