Getting the skinny on thick filament regulation in cardiac muscle biology and disease

Abstract

Thin (actin) filament accessory proteins are thought to be the regulatory force for muscle contraction in cardiac muscle; however, compelling new evidence suggests that thick (myosin) filament regulatory proteins are emerging as having independent and important roles in regulating cardiac muscle contraction. Key to these new findings is a growing body of evidence that point to an influential and more recently, direct role for ventricular myosin light chain-2 (MLC2v) phosphorylation in regulating cardiac muscle contraction, function and disease. This includes the discovery and characterization of a cardiac-specific myosin light chain kinase capable of phosphorylating MLC2v as well as a myosin phosphatase that dephosphorylates MLC2v in the heart, which provides added mechanistic insights on MLC2v regulation within cardiac muscle. Here we review evidence for an emerging and critical role for MLC2v phosphorylation in regulating cardiac myosin cycling kinetics, function and disease, based on recent studies performed in genetic mouse models and humans. We further provide new perspectives on future avenues for targeting these pathways as therapies in alleviating cardiac disease.

Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease

“…Identification of specific interactions between MLC-2 and the cardiac-specific domain of myosin binding protein C further suggested a role for MLC-2 in the myosin tail region, which has exposed binding sites for myosin binding protein C (Ratti et al, 2011). The association between regulatory proteins associated with cardiac myosin, which include a central role for MLC-2, has been detailed elsewhere (for review see Sheikh et al, 2014). …”

Comparative proteome analysis of saccular intracranial aneurysms with iTRAQ quantitative proteomics

“…Smooth muscle cell (SMC) can alter their phenotype from one primarily concerned with contraction to a proinflammatory and matrix remodeling phenotype, as a critical process in atherosclerosis and cerebral aneurysm [19]. Recent studies have supported that the conformational change induced by calcium binding or phosphorylation to RLC is a critical role in cardiac torsion, function and disease [20]. The expression levels of MYL2, which act downstream of the vascular smooth muscle contraction signal pathway and focal adhesion pathway, were significantly lower in sIAs tissue than those in the STA tissues (P b 0.05).…”

Constitutive Phosphorylation of Cardiac Myosin Regulatory Light Chain in Vivo

“…Ca 2ϩ dependence of myosin ATPase activity is conferred by the troponin complex, which regulates the availability of myosin binding sites on actin filaments (2). Contractile performance dependent on the actinmyosin system is modulated by phosphorylation of sarcomeric proteins, such as the troponin subunit troponin I (TnI) 2 in the actin thin filament as well as the myosin regulatory light chain (RLC) and myosin binding protein-C (MyBP-C), which are thought to control the position of myosin heads in the thick filament (3)(4)(5). Mutations in RLC, TnI, and MyBP-C are associated with cardiac myopathies, and changes in their phosphorylation are reported in human heart diseases, underscoring the importance of their modulatory roles (6,7).…”

“…Biochemically, cardiac RLC is phosphorylated by all three MLCKs and also zipper-interacting kinase (3,10). Selective ablation of the cardiac MLCK (cMLCK) gene, but not of the skeletal MLCK gene, decreases cardiac RLC phosphorylation from 0.45 to 0.10 mol of phosphate/mol of RLC, showing kinase-specific effects in the heart (3,5,9,(11)(12)(13)(14). This attenuation results in decreased cardiac performance and dilation of the adult mouse heart, not unlike the results obtained with knock-in mutant mice containing a nonphosphorylatable cardiac RLC.…”