Striated muscle proteins are regulated both by mechanical deformation and by chemical post-translational modification

Abstract

All cells sense force and build their cytoskeleton to optimize function. How is this achieved? Two major systems are involved. The first is that load deforms specific protein structures in a proportional and orientation-dependent manner. The second is post-translational modification of proteins as a consequence of signaling pathway activation. These two processes work together in a complex way so that local subcellular assembly as well as overall cell function are controlled. This review discusses many cell types but focuses on striated muscle. Detailed information is provided on how load deforms the structure of proteins in the focal adhesions and filaments, using α-actinin, vinculin, talin, focal adhesion kinase, LIM domain-containing proteins, filamin, myosin, titin, and telethonin as examples. Second messenger signals arising from external triggers are distributed throughout the cell causing post-translational or chemical modifications of protein structures, with the actin capping protein CapZ and troponin as examples. There are numerous unanswered questions of how mechanical and chemical signals are integrated by muscle proteins to regulate sarcomere structure and function yet to be studied. Therefore, more research is needed to see how external triggers are integrated with local tension generated within the cell. Nonetheless, maintenance of tension in the sarcomere is the essential and dominant mechanism, leading to the well-known phrase in exercise physiology: "use it or lose it."

Keywords: Adhesome; Costamere; Integrin; Mechanobiology; Mechanotransduction; Sarcomere.

Fig. 1

Structural deformation at rest compared to loaded states at the focal adhesion and costamere. (A) Talin binds to activated integrin at the focal adhesion (costamere in muscle) to stabilize actin filaments. With increased load, talin rod repeats unfold permitting vinculin association and strengthening actin anchoring. Other proteins like paxillin and focal adhesion kinase (FAK) are also recruited. High actin tension leads to recruitment of LIM-containing proteins like zyxin and FHL2. (B) Filamin dimers crosslink actin filaments. Interactions between the Ig-like domains become disrupted with increasing mechanical loads on actin. This untangling leads to exposure of cryptic binding sites of proteins like integrins

Fig. 2

Striated muscle proteins showing structural deformation at rest compared to loaded in the sarcomere. (A) The α-actinin and actin lattice is deformed when muscles go from a relaxed to contracting state leading to an increased actin-actin separation. (B) Titin N-terminal domain anchoring at the Z-disc exhibits a unilateral resistance to increased loads in the direction of contractile force by thin and thick filament sliding. (C) The titin kinase domain of striated muscle unfolds with high tension from actomyosin contraction leading to autophosphorylation and activation of hypertrophic signaling pathways. With excessive loads telethonin leads to p53 downregulation possibly via direct interactions with p53 and its cognate E3 ligase MDM2. (D) Myosin detachment rate from actin post-power stroke decreases with increased loads against the direction of the myosin level arm swinging

Fig. 3

Signaling pathways that affect protein modifications at their destination in muscle. In cardiac muscles, the ligands epinephrine and angiotensin II bind to the β1 adrenergic receptors (β1AR) and angiotensin II type 1 receptor (AT1R), respectively, activating second messengers such as cyclic AMP (cAMP) produced by adenylyl cyclase (AC), inositol 1,4,5-trisphosphate (IP3), and diacylglycerol (DAG) produced by phospholipase C (PLC). The signaling cascades proceed to activate other kinase enzymes, such as protein kinase A (PKA), protein kinase C epsilon (PKCε), protein kinase D (PKD) Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), and class IIa histone deacetylases (HDAC) that (de)-phosphorylate, (de)-acetylate cytoskeletal proteins. After ligand binding, G-protein-couple receptor inactivation begins by G protein-coupled receptor kinase(GRK) phosphorylation to promote β-arrestin. This leads to activation of other kinases such as extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p90 ribosomal S6 kinase 3 (RSK3) that modify sarcomeric proteins. Modifications by the signals for phosphorylation (P), acetylation (Ac), binding to phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), and PKCε binding at sarcomeric destinations are shown at the Z-disk where the actin capping protein CapZ is modified, and in the thin filament. Collectively, signals are integrated by the sarcomeric proteins to match muscle function to physiologic demand

Fig. 4

Integration of mechanical deformation and chemical signals in striated muscle. The effects of mechanical load and post-translational modification are shown diagrammatically with the resulting protein modifications by the signals for phosphorylation (P), acetylation (Ac), and binding of phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) to sarcomeric destinations. Mechanical loading alone triggers muscle hypertrophy, as does activation of the chemical signaling pathways alone. The mechanical loading is effective at the subcellular level near to the deformed proteins while the chemical signals is distributed throughout the cells. Thus, both local and whole cell response can be regulated