The sarcomeric cytoskeleton as a target for pharmacological intervention

TY - JOUR

T1 - The sarcomeric cytoskeleton as a target for pharmacological intervention

AU - Kho, Ay Lin

AU - Perera, Sue

AU - Alexandrovich, Alexander

AU - Gautel, Mathias

PY - 2012/6

Y1 - 2012/6

N2 - Many diseases of heart and skeletal muscle, from heart failure to muscle atrophy, pose unmet needs for specific and effective treatments. Recent advances suggest that sarcomeres, the smallest contractile units of heart and skeletal muscles, can be viable pharmacological targets. In sarcomeres, the contractile actin and myosin filaments are organised by a network of proteins combining structural and signalling functions, forming the sarcomeric cytoskeleton. This includes the giant proteins titin, obscurin and nebulin, which contain protein-binding sites along with signalling domains such as protein kinase, Rho activator, and Src-homology domains. These signalling domains have recently been implicated in sarcomere assembly, and the regulation of muscle contractile and metabolic adaptation. Although many functions of sarcomeric proteins remain to be discovered, their potential as pharmacological targets is now emerging. Here, we will review recent insight into the physiological and pathological signalling functions of sarcomeric cytoskeletal proteins and discuss new aspects and strategies in skeletal muscle signalling, pathomechanisms and therapy.

AB - Many diseases of heart and skeletal muscle, from heart failure to muscle atrophy, pose unmet needs for specific and effective treatments. Recent advances suggest that sarcomeres, the smallest contractile units of heart and skeletal muscles, can be viable pharmacological targets. In sarcomeres, the contractile actin and myosin filaments are organised by a network of proteins combining structural and signalling functions, forming the sarcomeric cytoskeleton. This includes the giant proteins titin, obscurin and nebulin, which contain protein-binding sites along with signalling domains such as protein kinase, Rho activator, and Src-homology domains. These signalling domains have recently been implicated in sarcomere assembly, and the regulation of muscle contractile and metabolic adaptation. Although many functions of sarcomeric proteins remain to be discovered, their potential as pharmacological targets is now emerging. Here, we will review recent insight into the physiological and pathological signalling functions of sarcomeric cytoskeletal proteins and discuss new aspects and strategies in skeletal muscle signalling, pathomechanisms and therapy.

U2 - 10.1016/j.coph.2012.03.007

DO - 10.1016/j.coph.2012.03.007

M3 - Article

SN - 1471-4892

VL - 12

SP - 347

EP - 354

JO - Current Opinion in Pharmacology

JF - Current Opinion in Pharmacology

IS - 3

ER -