Mechanosignaling pathways alter muscle structure and function by post-translational modification of existing sarcomeric proteins to optimize energy usage

Abstract

A transduced mechanical signal arriving at its destination in muscle alters sarcomeric structure and function. A major question addressed is how muscle mass and tension generation are optimized to match actual performance demands so that little energy is wasted. Three cases for improved energy efficiency are examined: the troponin complex for tuning force production, control of the myosin heads in a resting state, and the Z-disc proteins for sarcomere assembly. On arrival, the regulation of protein complexes is often controlled by post-translational modification (PTM), of which the most common are phosphorylation by kinases, deacetylation by histone deacetylases and ubiquitination by E3 ligases. Another branch of signals acts not through peptide covalent bonding but via ligand interactions (e.g. Ca²⁺ and phosphoinositide binding). The myosin head and the regulation of its binding to actin by the troponin complex is the best and earliest example of signal destinations that modify myofibrillar contractility. PTMs in the troponin complex regulate both the efficiency of the contractile function to match physiologic demand for work, and muscle mass via protein degradation. The regulation of sarcomere assembly by integration of incoming signaling pathways causing the same PTMs or ligand binding are discussed in response to mechanical loading and unloading by the Z-disc proteins CapZ, α-actinin, telethonin, titin N-termini, and others. Many human mutations that lead to cardiomyopathy and heart disease occur in the proteins discussed above, which often occur at their PTM or ligand binding sites.

Keywords: Mechanotransduction; Myofibrillogenesis; Phosphatidylinositol 4,5-bisphosphate; Proteomics; Signaling pathway.

Figure 1.. Convergence of mechanosignaling pathways on Z-disc proteins to modify their function by post-translational modification or binding to regulate adaptive remodeling of muscle mass.

Mechanical load deforms proteins in the focal adhesion and throughout the sarcomeric architecture, transducing into mechanosignaling pathways. These signals converge with other chemical pathways at the structural scaffolding of the Z-disc, depicted here by α-actinin (blue), the actin capping complex with CapZ (light blue), and actin (grey). At the Z-disc destination, these signals cause post-translational modification (PTM) of sarcomeric proteins by acetylation (Ac), ubiquitination (Ub), phosphorylation (Pi), and PIP2 binding. In this review, evidence supports that these PTMs initiate remodeling events. Atrophy arises from the lack of chemical and mechanical stimuli via protein ubiquitination and protease activity. Conversely, hypertrophy arises with increasing protein exchange and assembly for more Ac, Pi and PIP2.

Figure 2.. Modification sites of thin filament proteins at the Z-disc.

(A) The sarcomere is an array of thin and thick filaments bundled in parallel fashion by the Z-disc and the M-line proteins. This highly organized macromolecular assembly serves contractile function and distribution of mechanical forces longitudinally and laterally. Proteins highlighted in this review are the troponins, myosin, α-actinin, CapZ, telethonin and the titin N-terminus, depicted in blue. Crystal structures and linear sequences highlight protein subunits and domains are shown in panels BE. Linear sequences of protein complexes (domains and subunits color coded to show location of destination signals. (B) Myosin adopts a low-ATP consumption conformation (super relaxed state; PDB ID: 3JBH) that is restrained from interacting from actin and a high-ATP consumption conformation (disordered relaxed state; PDB ID: 3I5G) that interacts with actin (Alamo et al. 2016; Yang et al. 2007). The myosin essential (ELC) and regulatory (RLC) light chains associate to the level arm region. The RLC is susceptible to Ser 15 phosphorylation and Asn 14/16 deamination (Scruggs and Solaro 2011). (C) Molecular model of the core domain of troponin (TnC, green; TnI, red; TnT, blue in ribbon representations) bound to tropomyosin (white surface) and F-actin (grey surface) in the Ca²⁺-free state (PDB ID: 6KN7) (Yamada et al. 2020). (D) Muscle α-actinin (actin binding domain, red; neck region, yellow; spectrin-like repeats, green; calmodulin-like domain, magenta and purple) (Ribeiro et al. 2014) (PDB ID: 4D1E). (E) CapZ (α1 subunit, white; 1 subunit blue; β-tentacle in β1 subunit dark blue) (PDB ID: 1IZN) (Yamashita et al. 2003). (F) 1 telethonin: 2 titin N-terminal complex (titin N-terminal Z1, Z2 Ig-like repeats, blue; telethonin white) (PDB ID: 2F8V) (Reconditi et al. 2017).