Aug 2026· Cytoskeleton· pp.
e70187
· 0 citations· 67 references
Medicine
TL;DR
This review will discuss the general principles of myofibril assembly in the heart and cover new findings on myofibril maintenance and turnover.
Abstract
The assembly of actin and myosin to the paracrystalline arrangement of myofibrils in striated muscle, that is, heart and skeletal, has puzzled many a cell biologist. Different models, based on cultured cardiomyocytes, were proposed for the last 30 years to explain the sequence of events. These were then evaluated during heart development in embryos in situ and more recently in cardiomyocytes that were derived from human induced pluripotent stem cells (iPSC-CMs). A lot of the initial work was quite descriptive but recent advances in gene editing technology and in super resolution microscopy allow a more targeted functional analysis and will give unprecedented insight. This review will discuss the general principles of myofibril assembly in the heart and cover new findings on myofibril maintenance and turnover.
Emerging principles of myonuclear plasticity and spatial specialization are discussed, which reveal how myogenic nuclei undergo dynamic state transitions in response to interactions with surrounding cell types, and how these states can be remodeled during regeneration.
Minchul Kim, Yu Xin Wang, Nour El Khazen· Current Opinion in Genetics...· 1 citation
Background: Understanding the mechanisms of cardiomyocyte development is critical for fulfilling the potential of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Although myocyte development is known to depend on internal and external mechanical cues, further investigation is required to understand the contributions of different signals and how they are integrated together to generate an adult cardiomyocyte. Here, we address this gap by examining the role of calcium-activated contractility in sarcomere formation and maturation and its influence on the iPSC-CM response to nanopatterns. Methods: We generated iPSCs with homozygous D65A cardiac troponin C (cTnC) substitutions. This engineered cTnC cannot bind to calcium at site II, resulting in tropomyosin blocking strong myosin binding to the thin filament and inhibiting sarcomere contraction. The iPSCs were differentiated into cardiomyocytes and matured in culture over 60 days. Cells were characterized via imaging, metabolic assays, and calcium transient analysis. Proteomes were examined using mass spectrometry throughout differentiation and maturation. We also replated partially matured cardiomyocytes onto nanopatterned surfaces to investigate how external mechanical signals affect maturation in contractile versus non-contractile cells. Results: Surprisingly, we found that sarcomeres formed in the D65A cTnC cardiomyocytes, though these sarcomeres were underdeveloped and disorganized. The D65A cardiomyocytes also exhibited significant proteomic maturation defects and abnormal calcium transients. Replating the non-contractile cardiomyocytes onto nanopatterns improved several structural and proteomic maturation metrics. In contrast, WT maturation did not benefit from the introduction of nanopatterns. Conclusions: Calcium-activated contractility is dispensable for sarcomerogenesis but critical for cardiomyocyte maturation. In non-contractile, D65A cTnC cardiomyocytes, nanopatterns enhanced maturation, suggesting that external mechanical cues may partially compensate for defective contractility. However, nanopatterns did not facilitate WT maturation, suggesting that maturity may reduce the efficacy of nanopatterns. In addition to these novel findings, these mass spectrometry datasets cataloging iPSC-CM maturation represent a useful resource for the cardiovascular research community.
Laura A. Sherer, Abigail Nagle, M. Papadaki et al.· Circulation Research· 0 citations
In the presence of Fhod3, sarcomere reassembly after mitosis was successful, whereas it failed in the absence of Fhod3, indicating the indispensable role of Fhod3 in sarcomere reorganization after mitosis.
Shuhei Sakaguchi, Yohko Kage, Eka Adip Pradipta et al.· Cellular and Molecular Life...· 0 citations
Multiciliated cells, through the coordinated beating of motile cilia, are vital for moving fluids in the brain and mucus in the airways and in the reproductive organs. Their dysfunction leads to diseases, associated with chronic airway infections, subfertility and ventricular enlargement. A group of transcription factors and a cell cycle variant enable the differentiation of multiciliated cells. However, how the multiciliated differentiation programme is initiated, timed and spatially regulated within developing tissues remains unclear. In this review, we combine findings from airway, brain ventricles and Xenopus epidermal systems to reveal how mechanical cues may interact with transcriptional networks and cell cycle regulators during multiciliogenesis. We suggest a model where mechanical forces serve as contextual regulators that enable, time and control the execution of the multiciliated differentiation programme.
Nathalie Spassky, Nathalie Delgehyr· Open Biology· 0 citations
It is shown that microtubule expression and network density decline with cardiac maturation, which identifies microtubule networks as an essential regulator modulating CM dedifferentiation and sarcomere reorganization, which is critical for CM cytokinesis and cardiac regenerative repair.
Feng Zhang, Jenna Cusick, Jie Liang et al.· Circulation· 0 citations
Biallelic titin truncation variants (TTNtvs) are linked to severe cardiac and skeletal muscle diseases, due to unclear mechanisms. Using induced pluripotent stem cell-derived cardiomyocytes from a biallelic TTNtv patient with dilated cardiomyopathy, we investigated sarcomere structure/function. Only the longest of the TTNtvs was detected as protein, and this nearly full-length titin was incorporated into the sarcomere. Subtle structural alterations occurred, with shortened A-bands observed in a subset of sarcomeres. Resulting reduction and imbalance of force development was linked to lowered contractility, and many sarcomeres being stretched by their neighbors. Thus, inefficient sarcomere assembly and interaction promotes cardiomyopathy in biallelic TTNtv.
Magnhild Sekse Erdal, Jing Qi, P. Erusappan et al.· Journal of Molecular and Cel...· 0 citations
