The titin N2B and N2A regions: biomechanical and metabolic signaling hubs in cross-striated muscles

TY - JOUR

T1 - The titin N2B and N2A regions

T2 - biomechanical and metabolic signaling hubs in cross-striated muscles

AU - van der Pijl, Robbert J.

AU - Domenighetti, Andrea A.

AU - Sheikh, Farah

AU - Ehler, Elisabeth

AU - Ottenheijm, Coen A.C.

AU - Lange, Stephan

N1 - Funding Information: Open access funding is provided by the University of Gothenburg. This work was supported by grants from the NIH/NHLBI (HL128457, HL152251), the Swedish Heart-Lung Foundation and the Novo Nordisk Foundation (NNF20OC0062812) to S. Lange. The laboratory of C. Ottenheijm is supported by a grant from the NIH/NHLBI (HL121500). Work in the laboratory of E. Ehler is supported by the British Heart Foundation and by UKRI (MRC). Funding from the Shirley Ryan AbilityLab, the Department of Physical Therapy & Human Movement Sciences (PTHMS) at Northwestern University Feinberg School of Medicine, Cures Within Reach and the Pedal-with-Pete Foundation with the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) provides support for the work of A. Domenighetti. Grants by the NIH/NHLBI (HL142251 and HL145534) and the Department of Defense (W81XWH1810380) supported the work of F. Sheikh. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

KW - Mechanosensor

KW - Muscle

KW - Muscle mechanics

KW - Sarcomere

KW - Signaling

KW - Titin

UR - http://www.scopus.com/inward/record.url?scp=85114400203&partnerID=8YFLogxK

U2 - 10.1007/s12551-021-00836-3

DO - 10.1007/s12551-021-00836-3

M3 - Article

AN - SCOPUS:85114400203

SN - 1867-2450

VL - 13

SP - 653

EP - 677

JO - Biophysical Reviews

JF - Biophysical Reviews

IS - 5

ER -