Digital light processing 3D printing enables versatile fabrication of human engineered heart tissues

Cell Biomaterials · 2026-03-01

Force-Induced Ankle Opening Reveals Mechanical Stabilization of the Ankle of Human β-Cardiac Myosin

ACS Nano · 2026-05-21

Human β-cardiac myosin drives contraction in the heart. Extensive biophysical and single-molecule studies have quantified myosin’s chemo-mechanical cycle, which generates ∼5 nm of displacement and 5–7 pN of force. Myosin’s 9 nm-long, α-helical lever arm is rigidified by bound essential and regulatory light chains (ELC and RLC). Numerous pathogenic mutations and sequence-conservation patterns within the lever arm where the RLC binds (LARLC) belie the overly simplified view that the lever arm acts solely as a rigid rod that transduces ATP hydrolysis into motion. Structural studies have shown that myosin adopts an interacting-heads motif (IHM), which inhibits motor activity and mechanically strains the RLC complex, consisting of the RLC bound to the LARLC. Alteration in the configuration of the RLC complex’s “ankle”─a sharp kink in the lever arm─is hypothesized to modulate the propensity of myosin to enter the IHM. To investigate the complex’s mechanical stability, we developed a single-molecule atomic-force microscopy assay with three different pulling geometries: pulling across the LARLC, the RLC, and the RLC complex. When pulling across the LARLC by applying force to its N and C termini, the mechanical dissociation of the RLC was resolved along with two intermediates. Coarse-grained Brownian dynamics detailed these molecular configurations as the opening of myosin’s ankle and the preferential dissociation of one of the RLC’s two EF-hand domains. Moreover, the linker between the EF-hand domains forms an interface with an RLC N-terminal loop. This interface stabilized the native acute ankle angle against opening. Pulling across the RLC and the RLC complex revealed different unfolding pathways, each with one intermediate. Looking forward, these assays can probe for the effects of pathogenic mutations and phosphorylation on the nanomechanics of the RLC complex.

Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway

bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-11

Abstract Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response 1–3 . Using untargeted metabolomics, here we show that circulating levels of the metabolite para -tyramine-O-sulfate (pTOS) are increased >1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulfation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance.

Multi-omics Insight into Cardiac Myofibril Remodeling in Post-Prandial Burmese Pythons

bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-04

Burmese pythons exhibit rapid cardiac remodeling in response to a dramatic increase in metabolic rate during digestion. Here, we performed single-myofibril mechanics measurements and myosin heavy chain metabolic assays to evaluate the impact of feeding on the cardiomyocyte sarcomere - the fundamental molecular unit of muscle contraction - using two experimental paradigms: normal feeding (one meal per month) and frequent feeding (eight meals per month). Myofibril tension and rate of relaxation increased during digestion in both paradigms, while frequent feeding was further associated with slower myofibril activation kinetics and faster myosin heavy chain ATP turnover. To identify molecular changes at the sarcomere and gain potential mechanistic insight, we performed multi-omics analyses. RNA sequencing identified increased expression of some sarcomere genes during digestion; however, proteomics analysis suggested a delay in sarcomere protein synthesis at the peak of remodeling, as expression of many sarcomere proteins decreased. Analysis of post-translational modifications (ubiquitinomics, phospho-proteomics, acetylomics) identified hundreds of significantly regulated sites on sarcomere proteins during digestion, including many on the tension-regulating titin and myosin heavy chain proteins. Our results detail the molecular underpinnings of cardiac remodeling in digesting Burmese pythons and suggest that nature's solution for rapidly increasing cardiac contractility is a post-translational sarcomere tuning program.

EJHF expert consensus statement on the diagnosis and management of hypertrophic cardiomyopathy

European Journal of Heart Failure · 2026-01-06 · 2 citations

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic cardiac disease and a leading cause of heart failure, arrhythmia, and sudden cardiac death in both young and older adults. This consensus document was developed by a multidisciplinary panel of European and U.S. experts in HCM, imaging, electrophysiology, genetics, and heart failure. While it aligns with the 2023 ESC and 2024 AHA/ACC guidelines on HCM, the paper addresses areas where clinicians might require further guidance. Key sections include phenotypic classification, diagnostic strategies incorporating multimodal imaging and genetic testing, and risk stratification for sudden cardiac death. The document outlines therapeutic pathways for pharmacologic treatment, including beta-blockers, calcium channel blockers, disopyramide, and cardiac myosin inhibitors such as mavacamten and aficamten, as well as indications for septal reduction therapies. Management of atrial fibrillation, hypertension, coronary artery disease, pregnancy, paediatric HCM, and comorbidities is discussed in detail. Importantly, the consensus addresses current controversies including optimal risk stratification models, the care of genotype-positive/phenotype-negative individuals, and exercise recommendations. Finally, the manuscript highlights future directions such as gene therapy, precision medicine approaches, use of artificial intelligence and novel biomarkers for screening and diagnosis.

Python metabolomics uncovers a conserved postprandial metabolite and gut–brain feeding pathway

Nature Metabolism · 2026-03-19 · 1 citations

Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response1–3. Using untargeted metabolomics, we show that circulating levels of the metabolite para-tyramine-O-sulphate (pTOS) are increased more than 1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulphation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance. Leveraging pythons as an extreme model of feeding and fasting behaviour, this study uncovers para-tyramine-O-sulphate as a conserved postprandial metabolite that links nutrient intake to energy balance by activating hypothalamic neurons and suppressing food intake in pythons and mice.

Dynamic hyperplastic cardiac growth in Burmese pythons

bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-19

Cardiomyocytes hyperplasia is the primary form of fetal heart growth, whereas this proliferative capacity is largely lost in adults across most species. The limited ability of adult cardiomyocytes to re-enter the cell cycle is a major cause of cardiac injury-induced morbidity and mortality. Here, we report that post-prandial Burmese python cardiomyocytes activate cell cycle re-entry to promote persistent cardiac growth. Burmese pythons normally eat large meals infrequently, resulting in reversible cardiac hypertrophy. We found that frequent feeding of large meals amplifies the modest post-prandial cardiac proliferation identified in an infrequent feeding interval. By activating E2F and Forkhead Box M1 (FoxM1) pro-proliferation transcriptional networks, frequently fed Burmese pythons initiate cardiomyocyte hyperplasia. These findings identify hyperplasia as a natural means of sustained cardiac growth in Burmese pythons and support the use of pythons as a new model for investigating proliferative cardiac remodeling.

Longevity of cardiac and skeletal muscle proteins is dependent on tissue and subcellular compartmentation patterns

Cell Reports · 2025-12-31 · 1 citations

Myocytes are exceptionally long-lived cells that must maintain proteome integrity over decades while adjusting for changes in functional output and metabolic demand. We used in vivo stable isotope labeling combined with mass spectrometry proteomics and correlated multi-isotope imaging mass spectrometry to quantify and visualize protein turnover across cardiac, fast-twitch, and slow-twitch skeletal muscles, creating a resource of hundreds of individual protein turnover rates from each tissue. We found that cardiac muscle has the highest rate of protein turnover, followed by slow-twitch skeletal muscle and then fast-twitch skeletal muscle, and that these different rates of protein turnover are driven by different levels of muscle use, rather than myosin isoform composition. We also identified protein age heterogeneity at the myofiber and sarcomere levels. These findings uncover fundamental principles of muscle protein maintenance and have broad implications for understanding cellular aging, muscle disease, and the design of therapeutic strategies targeting muscle protein turnover.

Age-Dependent Mechanisms of Cardiac Hypertrophy Regression Following Exercise in Female Mice

bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-11 · 2 citations

ABSTRACT Cardiac adaptation to exercise is a fundamental physiological process, but its regression and the underlying molecular mechanisms, particularly in relation to age, remain poorly understood. This study investigated the age-dependent differences in cardiac remodeling and molecular signaling during exercise training and detraining in young (5-week-old) and adult (24-week-old) female mice, focusing specifically on how cardiac plasticity changes with adulthood rather than senescence. While both age groups exhibited significant cardiac hypertrophy after the exercise period, young mice displayed significantly more hypertrophic growth (23% increase in left ventricular mass versus 15% in adults). During detraining, cardiac mass regression occurred more rapidly in young mice. Transcriptomic analysis revealed distinct gene expression profiles between age groups, with changes in metabolic and autophagy pathways. Notably, ERK1/2 phosphorylation increased significantly during exercise in young but not adult hearts, correlating with elevated expression of well-known genes associated with exercise, namely CITED4 and SOD2. Furthermore, increased LC3-II/LC3-I ratio and AMPK phosphorylation were observed exclusively in young mice during detraining, indicating age-specific activation of autophagy-mediated cardiac remodeling. These findings demonstrate that cardiac adaptability to exercise and detraining follows distinct molecular pathways in young versus adult mice, with the younger heart exhibiting greater plasticity through enhanced ERK signaling during hypertrophy and autophagy during regression. This age-dependent cardiac plasticity may have important implications for understanding the cardiovascular benefits of exercise across the lifespan and developing age-appropriate exercise recommendations.

Genome report: first whole genome assembly of <i>Python regius</i> (ball python), a model of extreme physiological and metabolic plasticity

G3 Genes Genomes Genetics · 2025-09-02 · 1 citations

The study of nontraditional model organisms, particularly those exhibiting extreme phenotypes, offers unique insights into adaptive mechanisms of stress response and survival. Snakes, with their remarkable physiological, metabolic, and morphological adaptations, serve as powerful models for investigating these processes. Burmese pythons (Python bivittatus) have been used as a model for studying the plasticity of extreme physiological systems. The low contiguity of the P. bivittatus genome and rising challenges in obtaining Burmese pythons for study prompted us to sequence, assemble, and annotate the genome of the closely related ball python (Python regius). Using a hybrid sequencing approach, we generated a 1.45-Gb genome assembly with a scaffold N50 greater than 61 Mb and a benchmarking universal single-copy ortholog (BUSCO) score of 98%, representing one of the highest quality genomes to date for a member of the Pythonidae family. This assembly provides a valuable resource for studying snake-specific traits and evolutionary biology. Furthermore, it enables exploration of the molecular mechanisms underlying the remarkable cardiac and muscular adaptations in pythons, such as their ability to rapidly remodel their heart following feeding and resist muscular atrophy during prolonged fasting. These insights have potential applications in human health, particularly in the development of therapies targeting cardiac hypertrophy and muscular atrophy.