Titin, a Central Mediator for Hypertrophic Signaling, Exercise-Induced Mechanosignaling and Skeletal Muscle Remodeling

Abstract

Titin is a giant scaffold protein with multiple functions in striated muscle physiology. Due to the elastic I-band domains and the filament-like integration in the half-sarcomere titin is an important factor for sarcomere assembly and serves as an adaptable molecular spring that determines myofilament distensibility. Protein-interactions e.g., with muscle ankyrin repeat proteins or muscle LIM-protein link titin to hypertrophic signaling and via p62 and Muscle Ring Finger proteins to mechanisms that control protein quality control. This review summarizes our current knowledge on titin as a central node for exercise-induced mechanosignaling and remodeling and further highlights the pathophysiological implications.

Keywords: connection; hypertrophic signaling; passive tension; posttranslational modification; striated muscle.

Figure 1

Scheme of titin-domain architecture (N2A-isoform of human skeletal muscle) in a half-sarcomere with selected titin ligands and titin-based signaling. Numbers indicate six superrepeats with seven modular domains and 11 superrepeats with 11 modular domains within the thick filament-associated A band titin. T-CAP, telethonin (titin-cap); FHL2, four-and-a-half LIM domain protein 2; Nbr1, neighbor-of-BRCA1-gene-1; MURFs, Muscle RING finger proteins 1/2; Mdm2, mouse double minute-2 protein; MARPs, muscle ankyrin repeat domain proteins; PKCα, Ca2+-dependent protein kinase α; CaMKII δ, Ca2+/calmodulin-dependent protein kinase II δ; MyBP-C, myosin-binding protein C; MHC, myosin heavy chain; ATE1, Arginine-tRNA-protein transferase 1; P, phosphorylation site; Immunoglobulin-like domains (white bars); Fibronectin-like domains (red bars), unique sequences (blue bars), PEVK-elements (yellow bars), Z-repeats (green bar), TK, titin kinase domain.

Figure 2

Scheme of titin involvement in muscle adaptation after acute and chronic exercise. The scheme summarizes the current knowledge and the different levels of stimuli that modulate titin turnover and titin-based myofilament stiffness in response to acute or repeated exercise. It further highlights the interplay of different signaling pathways that link titin to exercise-induced remodeling processes.