Houda Cohen

The landscape of human cardiac biology was transformed by the discovery that adult somatic cells can be reprogrammed into induced pluripotent stem cells, enabling patient-specific disease modeling, drug testing, and regenerative strategies without the prior ethical or biological constraints. Subsequent advances in directed differentiation made the generation of human iPSC-derived cardiac myocytes reliable and scalable. Despite this progress, a central limitation has remained: these cells are developmentally immature, resembling fetal cardiac myocytes in structure, metabolism, and function. This immaturity restricts their utility for modeling adult-onset disease, predicting drug responses, and achieving clinical translation. Maturation is now understood as a multifactorial symphony, requiring coordinated molecular, structural, and environmental inputs rather than single interventions. As a result, the field is shifting toward integrative approaches that incorporate 3D architecture, multicellular systems, and biomimetic environments to better replicate native cardiac tissue. While fully adult-like myocardium remains an ongoing goal, advances in bioengineering and system-level design are narrowing the gap, with success increasingly defined by the generation of functional cardiac tissue rather than isolated cell maturity.

The cardiac sarcomere is a triumph of biological evolution wherein myriad contractile and regulatory proteins assemble into a quasi-crystalline lattice to serve as the central point upon which cardiac muscle contraction occurs. This review focuses on the many signaling components and mechanisms of regulation that impact cardiac sarcomere function. We highlight the roles of the thick and thin filament, both as necessary structural and regulatory building blocks of the sarcomere as well as targets of functionally impactful modifications. Currently, a new focus emerging in the field is inter-myofilament signaling, and we discuss here the important mediators of this mechanism, including myosin-binding protein C and titin. As the understanding of sarcomere signaling advances, so do the methods with which it is studied. This is reviewed here through discussion of recent live muscle systems in which the sarcomere can be studied under intact, physiologically relevant conditions.

In the failing heart, the cardiac myocyte microtubule network is remodeled, which increases cellular stiffness and disrupts contractility, contributing to heart failure and death. However, the origins of this deleterious cytoskeletal reorganization are unknown. We now find that oxidative stress, a condition characteristic of failing heart cells, leads to cysteine oxidation of microtubules. Further, our electron and fluorescence microscopy experiments revealed regions of structural damage within the oxidized microtubule lattice. These damaged regions led to the lengthening, realignment, and acetylation of dynamic microtubules within cardiac myocytes. Thus, we found that oxidative stress acts inside of cardiac myocytes to facilitate a dramatic, pathogenic shift from a dynamic, multifaceted microtubule network into a highly acetylated, longitudinally aligned, and static microtubule network. Our results demonstrate how a disease condition characterized by oxidative stress can trigger a molecular oxidation event, which propagates a toxic cellular-scale transformation of the cardiac myocyte microtubule network.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.