Cardiac sarcomere mechanics in health and disease

Abstract

The sarcomere is the fundamental structural and functional unit of striated muscle and is directly responsible for most of its mechanical properties. The sarcomere generates active or contractile forces and determines the passive or elastic properties of striated muscle. In the heart, mutations in sarcomeric proteins are responsible for the majority of genetically inherited cardiomyopathies. Here, we review the major determinants of cardiac sarcomere mechanics including the key structural components that contribute to active and passive tension. We dissect the molecular and structural basis of active force generation, including sarcomere composition, structure, activation, and relaxation. We then explore the giant sarcomere-resident protein titin, the major contributor to cardiac passive tension. We discuss sarcomere dynamics exemplified by the regulation of titin-based stiffness and the titin life cycle. Finally, we provide an overview of therapeutic strategies that target the sarcomere to improve cardiac contraction and filling.

A Comprehensive Outlook on Dilated Cardiomyopathy (DCM): State-Of-The-Art Developments with Special Emphasis on OMICS-Based Approaches

“…DCM progression is initiated by various genetic and idiopathic factors. Classically, “Frank-Starling law” described the causal relationship between resultant contraction force with cardiac fiber length [ 70 ]. Mutations in sarcomeric, non-sarcomeric and cytoskeletal protein components have been attributed mechanically to cardiac contraction reduction during DCM [ 33 ].…”

Nanosurgical Manipulation of Titin and Its M-Complex

“…Its multidomain architecture makes it one of the most versatile proteins of the sarcomere [3]. Titin's physical role is to align and stabilize the sarcomere and maintain its geometric symmetry [4]. Besides its mechanical functions, titin is also thought to be important in providing a blueprint for sarcomeric organization [5][6][7] and sensing the sarcomere's contractile status [8][9][10].…”

“…Furthermore, titin has been suggested to contribute to active muscle force generation driven by rapid refolding of its globular domains [12][13][14]. Titin's numerous functions explain the increasing recognition of its contribution to a number of diseases [2,4]. Structurally, titin is woven into the M-band in the middle of the sarcomere [15,16].…”

The road to physiological maturation of stem cell-derived cardiac muscle runs through the sarcomere

“…Fundamental to the sarcomere are its regulatory, structural and effector functions [11][12][13]. The sarcomere consists of a highly organized assembly of literally millions (if not more) of individual contractile and regulatory proteins highly organized into inter-digitating thin and thick myofilaments, together with a host of Z-line and M-line proteins and elastic elements (titin).…”