Cardiac microtubules in health and heart disease

Abstract

Cardiomyocytes are large (∼40,000 µm3), rod-shaped muscle cells that provide the working force behind each heartbeat. These highly structured cells are packed with dense cytoskeletal networks that can be divided into two groups—the contractile (i.e. sarcomeric) cytoskeleton that consists of filamentous actin-myosin arrays organized into myofibrils, and the non-sarcomeric cytoskeleton, which is composed of β- and γ-actin, microtubules, and intermediate filaments. Together, microtubules and intermediate filaments form a cross-linked scaffold, and these networks are responsible for the delivery of intracellular cargo, the transmission of mechanical signals, the shaping of membrane systems, and the organization of myofibrils and organelles. Microtubules are extensively altered as part of both adaptive and pathological cardiac remodeling, which has diverse ramifications for the structure and function of the cardiomyocyte. In heart failure, the proliferation and post-translational modification of the microtubule network is linked to a number of maladaptive processes, including the mechanical impediment of cardiomyocyte contraction and relaxation. This raises the possibility that reversing microtubule alterations could improve cardiac performance, yet therapeutic efforts will strongly benefit from a deeper understanding of basic microtubule biology in the heart. The aim of this review is to summarize the known physiological roles of the cardiomyocyte microtubule network, the consequences of its pathological remodeling, and to highlight the open and intriguing questions regarding cardiac microtubules. Impact statement Advancements in cell biological and biophysical approaches and super-resolution imaging have greatly broadened our view of tubulin biology over the last decade. In the heart, microtubules and microtubule-based transport help to organize and maintain key structures within the cardiomyocyte, including the sarcomere, intercalated disc, protein clearance machinery and transverse-tubule and sarcoplasmic reticulum membranes. It has become increasingly clear that post translational regulation of microtubules is a key determinant of their sub-cellular functionality. Alterations in microtubule network density, stability, and post-translational modifications are hallmarks of pathological cardiac remodeling, and modified microtubules can directly impede cardiomyocyte contractile function in various forms of heart disease. This review summarizes the functional roles and multi-leveled regulation of the cardiac microtubule cytoskeleton and highlights how refined experimental techniques are shedding mechanistic clarity on the regionally specified roles of microtubules in cardiac physiology and pathophysiology.