Biology subjects

Leinwand, L. A.

Publications and source records attributed to Leinwand, L. A..

At least 19 recordsLinked to original sources

bioRxiv2026

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

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 natures solution for rapidly increasing cardiac contractility is a post-translational sarcomere tuning program.

molecular biology↗

bioRxiv2026

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

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, 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.

physiology↗

bioRxiv2025

Fiber Type and Stimulus Determine Progression of Skeletal Muscle Atrophy

BackgroundSkeletal muscle atrophy is prevalent worldwide and is a major detractor from length and quality of life. It is often diagnosed and treated as a single disorder, but the causal stimuli and progression of atrophy vary widely. Malnutrition and disuse are two common causes of muscle atrophy, and despite their prevalence and extensive characterization, there have been no direct comparisons of how these two types of atrophy progress and whether they differentially affect skeletal muscle fiber types. The purpose of this study is to directly compare atrophy from fasting and disuse and provide a transcriptomic resource for future research on both conditions. MethodsWe fasted or hindlimb suspended (HS) two cohorts of 12-week-old female C57/bl6 mice. Mice were fasted for up to 72 hours to induce malnutrition atrophy or were hindlimb suspended for 0, 3, 7, 14, or 28 days to induce disuse atrophy. At each timepoint, mice were euthanized and three muscles (tibialis anterior (TA), extensor digitorum longus (EDL), and soleus) were weighed and collected for RNA sequencing. Atrophy progression and gene expression changes were compared across muscle fiber types and atrophy stimuli. ResultsWe found differences in atrophy progression between muscle fiber types based on fiber twitch speed and atrophy stimulus. Fasted mice lost 25% of their body weight and 23% of fast-twitch TA mass with little change in soleus. In contrast, HS mice lost 40% of the slower-twitch soleus but the effect on the TA was negligible. Gene expression varied in response to both atrophy stimuli, but a greater number of genes changed with fasting compared to HS in the EDL and soleus. By muscle type, a greater transcriptional shift occurred in the EDL with fasting while the soleus showed more gene changes during HS. Enrichment analysis of transcriptional changes showed similarities (downregulation in muscle growth pathways) and differences (increased fatty acid metabolism in fasting and increased neuronal activity in HS) between atrophy stimuli. ConclusionsAtrophy progression varies based on stimuli and muscle fiber type. This study provides a large, matched data set where the effects of different atrophic stimuli can be easily and directly compared in multiple fiber types. To our knowledge, this is the first study to closely compare these two atrophy stimuli in a muscle type-specific context. This work demonstrates that atrophy is not a single disorder and that the development of therapies may need to be tailored to the atrophic stimulus.

molecular biology↗

bioRxiv2025

Cytoplasmic CaMKIIδ-B prevents myocardial recovery in heart failure

Restoration of cardiac function in patients with advanced heart failure is rare, and the molecular processes that regulate recovery are unknown. To identify potential mechanisms, we studied paired myocardial samples before and after left ventricular assist device therapy, where significant cardiac functional recovery occurred in [~]25% of patients. We found that expression of the nuclear B isoform of Ca2+/calmodulin-dependent protein kinase II{delta} (CaMKII{delta}-B) inversely correlated with recovery. Furthermore, increased phosphorylation near the CaMKII{delta}-B nuclear localization signal in non-responders prevented its auto-activation dependent nuclear translocation. Expression of a cytoplasm-restricted CaMKII{delta}-B in cardiomyocytes dramatically remodeled the phospho-proteome and impaired contractility, while a nuclear-competent version did not. Modulating CaMKII{delta} subcellular localization may thus represent a therapeutic strategy for advanced heart failure.

physiology↗

bioRxiv2025

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

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.

physiology↗

bioRxiv2025

First whole genome assembly of Python regius (ball python), a model of extreme physiological and metabolic plasticity

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. Pythons are a unique model organism that have been studied for their extreme metabolic and physiological plasticity. To date, the Burmese python (Python bivittatus) is the only member of the Pythonidae family to have been sequenced. The low contiguity of this 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 contig N50 greater than 18 Mb and a BUSCO score of 98%, representing the highest quality genome 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 organs 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.

genomics↗

bioRxiv2024

Digital Light Processing 3D Printing enables High Throughput Fabrication of Human Engineered Heart Tissues for Disease Modeling

3D in vitro engineered heart tissue (EHT) models recapitulate aspects of native cardiac physiology but are often limited by scalability, cost, and reproducibility. Here, we report a simple, one-step method for rapid ([~]minutes) fabrication of molds using digital light processing (DLP)-based 3D printing that support the formation of EHTs by human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with high reproducibility (>95% efficiency) and varied designs (e.g., length, aspect ratio). Compared to 2D iPSC-CMs, 3D EHTs display enhanced maturity, including increased expression of {beta}-oxidation genes, higher concentrations of sarcomeric myosins, improved sarcomere density and alignment, and enrichment of cardiac pathways (e.g., upregulation of sodium channels, action potentials, contraction). The technology is applied to model pathological cardiac hypertrophy in vitro, using either (i) acute adrenergic agonism or (ii) chronic culture within stiff hydrogel molds. Treated EHTs exhibit increased levels of pathology-associated gene expression and activation of signaling cascades involved in pathological remodeling compared to untreated controls or treated 2D iPSC-CMs. Thus, our method results in robust yet simpler, cheaper, and faster EHTs to study cardiac disease.

bioengineering↗

bioRxiv2024

A Conserved Mechanism of Cardiac Hypertrophy Regression through FoxO1

The heart is a highly plastic organ that responds to diverse stimuli to modify form and function. The molecular mechanisms of adaptive physiological cardiac hypertrophy are well-established; however, the regulation of hypertrophy regression is poorly understood. To identify molecular features of regression, we studied Burmese pythons which experience reversible cardiac hypertrophy following large, infrequent meals. Using multi-omics screens followed by targeted analyses, we found forkhead box protein O1 (FoxO1) transcription factor signaling, and downstream autophagy activity, were downregulated during hypertrophy, but re-activated with regression. To determine whether these events were mechanistically related to regression, we established an in vitro platform of cardiomyocyte hypertrophy and regression from treatment with fed python plasma. FoxO1 inhibition prevented regression in this system, while FoxO1 activation reversed fed python plasma-induced hypertrophy in an autophagy-dependent manner. We next examined whether FoxO1 was implicated in mammalian models of reversible hypertrophy from exercise and pregnancy and found that in both cases FoxO1 was activated during regression. In these models, as in pythons, activation of FoxO1 was associated with increased expression FoxO1 target genes involved in autophagy. Taken together, our findings suggest FoxO1-dependent autophagy is a conserved mechanism for regression of physiological cardiac hypertrophy across species. HIGHLIGHTSO_LIPost-prandial cardiac remodeling in Burmese pythons is associated with dynamic regulation of FoxO1 and autophagy. C_LIO_LIRegression of fed python plasma-induced hypertrophy in mammalian cardiomyocytes is FoxO1-dependent. C_LIO_LIActivation of FoxO1-dependent autophagy is a conserved feature of physiological hypertrophy regression in mammalian models. C_LI

physiology↗

bioRxiv2023

Divergent Molecular Phenotypes in Point Mutations at the Same Residue in Beta-Myosin Heavy Chain Lead to Distinct Cardiomyopathies

In genetic cardiomyopathies, a frequently described phenomenon is how similar mutations in one protein can lead to discrete clinical phenotypes. One example is illustrated by two mutations in beta myosin heavy chain ({beta}-MHC) that are linked to hypertrophic cardiomyopathy (HCM) (Ile467Val, I467V) and left ventricular non-compaction (LVNC) (Ile467Thr, I467T). To investigate how these missense mutations lead to independent diseases, we studied the molecular effects of each mutation using recombinant human {beta}-MHC Subfragment 1 (S1) in vitro assays. Both HCM-I467V and LVNC-I467T S1 mutations exhibited similar mechanochemical functions, including unchanged ATPase and enhanced actin velocity but had distinct effects on the basal activity of myosin. HCM-I467V S1 showed no change in basal ATPase activity of myosin while LVNC-I467T reduced the basal ATPase activity by 50%. Molecular dynamics simulations reveal that I467T allosterically disrupts nucleotide binding of myosin, which may contribute to the uncoupled reduced basal activity and enhanced actin velocity observed in this mutation. These contrasting molecular effects may lead to contractile dysregulation that initiates LVNC-associated signaling pathways that progress the phenotype. Together, analysis of these mutations provides evidence that phenotypic complexity originates at the molecular level and is critical to understanding disease progression and developing therapies.

biophysics↗

bioRxiv2023

Homologous mutations in β, embryonic, and perinatal muscle myosins have divergent effects on molecular power generation

Mutations at a highly conserved homologous residue in three closely related muscle myosins cause three distinct diseases involving muscle defects: R671C in {beta}-cardiac myosin causes hypertrophic cardiomyopathy, R672C and R672H in embryonic skeletal myosin cause Freeman Sheldon syndrome, and R674Q in perinatal skeletal myosin causes trismus- pseudocamptodactyly syndrome. It is not known if their effects at the molecular level are similar to one another or correlate with disease phenotype and severity. To this end, we investigated the effects of the homologous mutations on key factors of molecular power production using recombinantly expressed human {beta}, embryonic, and perinatal myosin subfragment-1. We found large effects in the developmental myosins, with the most dramatic in perinatal, but minimal effects in {beta} myosin, and magnitude of changes correlated partially with clinical severity. The mutations in the developmental myosins dramatically decreased the step size and load-sensitive actin-detachment rate of single molecules measured by optical tweezers, in addition to decreasing ATPase cycle rate. In contrast, the only measured effect of R671C in {beta} myosin was a larger step size. Our measurements of step size and bound times predicted velocities consistent with those measured in an in vitro motility assay. Finally, molecular dynamics simulations predicted that the arginine to cysteine mutation in embryonic, but not {beta}, myosin may reduce pre-powerstroke lever arm priming and ADP pocket opening, providing a possible structural mechanism consistent with the experimental observations. This paper presents the first direct comparisons of homologous mutations in several different myosin isoforms, whose divergent functional effects are yet another testament to myosins highly allosteric nature.

biophysics↗

bioRxiv2022

Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least 6 of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 milliseconds of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatins binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R2=0.82). To test our ability to make blind predictions, we predicted blebbistatins binding affinity for an isoform (Myh7b) whose blebbistatin sensitivity was unknown. Encouragingly, we find good agreement between the predicted and measured IC50 (0.67 {micro}M vs. 0.36 {micro}M). Therefore, we expect this framework to be useful for the development of novel specific drugs across numerous protein targets. SignificanceDrug development requires the discovery of compounds which specifically target one member of a protein family without triggering side effects that arise from interactions with other related proteins. Myosins are a family of motor proteins that are drug targets for heart diseases, cancer, and parasitic infections. Here, we investigate why the compound blebbistatin specifically inhibits some myosins more potently than others, even though its binding site is closed in all known experimental structures. We find that the blebbistatin binding pocket opens in molecular dynamics simulations of certain myosin motors, and that the probability of opening predicts how potently blebbistatin inhibits a particular motor. Our work suggests that differences in cryptic pocket formation can be exploited to develop specific therapeutics.

biophysics↗

bioRxiv2020

Myosin 7b is a regulatory long noncoding RNA (lncMYH7b) in the human heart

Myosin heavy chain 7b (MYH7b) is an ancient member of the myosin heavy chain motor protein family that is expressed in striated muscles. In mammalian cardiac muscle, MYH7b RNA is expressed along with two other myosin heavy chains, {beta}-myosin heavy chain ({beta}-MyHC) and -myosin heavy chain (a-MyHC). However, unlike {beta}-MyHC and -MyHC which are maintained in a careful balance at the protein level, the MYH7b locus does not produce protein in the heart due to a post-transcriptional exon-skipping mechanism that occurs in a tissue specific manner. Whether this locus has a role in the heart beyond producing its intronic microRNA, miR-499, was unclear. Using cardiomyocytes derived from human induced pluripotent stem cells as a model system, we have found that the non-coding exon skipped RNA (lncMYH7b) affects the transcriptional landscape of the human heart, independent of miR-499. Specifically, lncMYH7b regulates the ratio of {beta}-MyHC to -MyHC, which is crucial for heart function. This regulation is likely achieved through control of members of the TEA domain transcription factor family (TEAD1 and TEAD3). Therefore, we conclude that this ancient gene has been repurposed by alternative splicing to produce a regulatory long-noncoding RNA in the human heart that affects the myosin composition of the heart.

molecular biology↗

bioRxiv2019

Novel model of distal myopathy caused by the myosin rod mutation R1500P disrupts acto-myosin binding

IntroductionMore than 400 mutations in {beta}-myosin, a slow myosin motor, can cause both cardiac and skeletal myopathy in humans. A small subset of these mutations, mostly located in the myosin rod, leads to a progressive skeletal muscle disease known as Laing distal myopathy (MPD1). While this disease has previously been studied using a variety of systems, it has never been studied in the mammalian muscle environment. Here, we describe a mouse model for the MPD1-causing mutation R1500P to elucidate disease pathogenesis and to act as a future platform for testing therapeutic interventions.\n\nMethodsBecause mice have very few slow skeletal muscles compared to humans, we generated mice expressing the {beta}-myosin R1500P mutation or WT {beta}-myosin in fast skeletal muscle fibers and determined the structural and functional consequences of the R1500P mutation.\n\nResultsThe mutant R1500P myosin affects both muscle histological structure and function and the mice exhibit a number of the histological hallmarks that are often identified in patients with MPD1. Furthermore, R1500P mice show decreased muscle strength and endurance, as well as ultrastructural abnormalities in the SR & t-tubules. Somewhat surprisingly because of its location in the rod, the R1500P mutation weakens acto-myosin binding by affecting cross-bridge detachment rate.\n\nConclusionsWhile each group of MPD1-causing mutations most likely operates through distinct mechanisms, our model provides new insight into how a mutation in the rod domain impacts muscle structure and function and leads to disease.

molecular biology↗

bioRxiv2019

miR-206 enforces a slow muscle phenotype

Striated muscle is a highly specialized collection of tissues with contractile properties varying according to functional needs. Although muscle fiber types are established postnatally, lifelong plasticity facilitates stimulus-dependent adaptation. Functional adaptation requires molecular adaptation, partially provided by miRNA-mediated post-transcriptional regulation. miR-206 is a muscle-specific miRNA enriched in slow muscles. We investigated whether miR-206 drives the slow muscle phenotype or is merely an outcome. We found that miR-206 expression increases in both physiologic (including female sex and endurance exercise) and pathologic conditions that promote a slow phenotype. Consistent with that observation, the slow soleus muscle of male miR-206 knockout mice displays a faster phenotype than wild-type mice. Moreover, their left ventricles have a faster myosin profile accompanied by male-specific dilation and systolic dysfunction. Thus, miR-206 appears necessary to enforce a slow skeletal and cardiac muscle phenotype and to play a key role in muscle sexual dimorphisms.

molecular biology↗

bioRxiv2019

miR-1/206 down-regulates splicing factor Srsf9 to promote myogenesis

BackgroundMyogenesis is driven by specific changes in the transcriptome that occur during the different stages of muscle differentiation. In addition to controlled transcriptional transitions, several other post-transcriptional mechanisms direct muscle differentiation. Both alternative splicing and miRNA activity regulate gene expression and production of specialized protein isoforms. Importantly, disruption of either process often results in severe phenotypes as reported for several muscle diseases. Thus, broadening our understanding of the post-transcriptional pathways that operate in muscles will lay the foundation for future therapeutic interventions.\n\nMethodsWe employed bioinformatics analysis in concert with the well-established C2C12 cell system for predicting and validating novel miR-1 and miR-206 targets engaged in muscle differentiation. We used reporter gene assays to test direct miRNA targeting and studied C2C12 cells stably expressing one of the cDNA candidates fused to a heterologous, miRNA-resistant 3 UTR. We monitored effects on differentiation by measuring fusion index, myotube area, and myogenic gene expression during time course differentiation experiments.\n\nResultsGene ontology analysis revealed a strongly enriched set of putative miR-1 and miR-206 targets associated with RNA metabolism. Notably, the expression levels of several candidates decreased during C2C12 differentiation. We discovered that the splicing factor Srsf9 is a direct target of both miRNAs during myogenesis. Persistent Srsf9 expression during differentiation impaired myotube formation and blunted induction of the early pro-differentiation factor myogenin as well as the late differentiation marker sarcomeric myosin, Myh8.\n\nConclusionsOur data uncover novel miR-1 and miR-206 cellular targets and establish a functional link between the splicing factor Srsf9 and myoblast differentiation. The finding that miRNA-mediated clearance of Srsf9 is a key myogenic event illustrates the coordinated and sophisticated interplay between the diverse components of the gene regulatory network.

cell biology↗

bioRxiv2019

Cardiac myocytes respond differentially and synergistically to matrix stiffness and topography

During cardiac disease progression, myocytes undergo molecular, functional and structural changes, including increases in cell size and shape, decreased myocyte alignment and contractility. The heart often increases extracellular matrix production and stiffness, which affect myocytes. The order and hierarchy of these events remain unclear as available in vitro cell culture systems do not adequately model both physiologic and pathologic environments. Traditional cell culture substrates are 5-6 orders of magnitude stiffer than even diseased native cardiac tissue. Studies that do account for substrate stiffness often do not consider intercellular alignment and vice versa. We developed a cardiac myocyte culture platform that better recapitulates native tissue stiffness while simultaneously introducing topographical cues that promote cellular alignment. We show that stiffness and topography impact myocyte molecular and functional properties. We used a spatiotemporally-tunable, photolabile hydrogel platform to generate a range of stiffness and micron-scale topographical patterns to guide neonatal rat ventricular myocyte morphology. Importantly, these substrate patterns were of subcellular dimensions to test whether cells would spontaneously respond to topographical cues rather than an imposed geometry. Cellular contractility was highest and the gene expression profile was most physiologic on gels with healthy cardiac tissue stiffness. Surprisingly, while elongated patterns in stiff gels yielded the greatest cellular alignment, the cells actually had more pathologic functional and molecular profiles. These results highlight that morphological measurements alone are not a surrogate for overall cellular health as many studies assume. In general, substrate stiffness and micropatterning synergistically affect cardiac myocyte phenotype to recreate physiologic and pathologic microenvironments.\n\nSignificance StatementHeart disease is accompanied by organ- and cellular-level remodeling, and deconvoluting their interplay is complex. Cellular-level change is best studied in vitro due to greater control and uniformity of cell types compared to animals. One common metric is degree of cellular alignment as misalignment of myocytes is a hallmark of disease. However, most studies utilize featureless culture surfaces that are orders of magnitude stiffer than, and do not mimic the scaffolding of, the heart. We developed a hydrogel platform with tunable stiffness and patterns providing topographical alignment cues. We cultured heart cells on and characterized multifactorial responses to these dynamic surfaces. Interestingly, conditions that yielded greatest alignment did not yield the healthiest functional and molecular state. Thus, morphology alone is not an indicator of overall cellular health.

cell biology↗

bioRxiv2019

Regression from pathological hypertrophy is sexually dimorphic and stimulus-specific

AimsPathological cardiac hypertrophy is the result of increased cardiomyocyte size, leading to thickening of the left ventricular walls and a decrease in the left ventricular chamber. With early treatment of the underlying cause, cardiac hypertrophy can be reversed in some individuals, while it persists in others. Here, we investigate mechanisms leading to regression of pathological cardiac hypertrophy in two mouse models, in addition to defining the sex differences associated with hypertrophy and regression.\n\nMethods and ResultsTwo pathological hypertrophic stimuli were used in male and female mice (Isoproterenol or Angiotensin II). The stimulus was removed after 7 days of treatment, then the left ventricle was studied at intervals up to 7 days following the removal of the stimulus. Following Isoproterenol removal, male hearts returned to baseline sizes in 4 days while it took 7 days for female hearts to regress. After Angiotensin II removal, the left ventricular masses of males and females did not regress. ERK1/2 was activated in response to both Isoproterenol and Angiotensin II in males, then decreased back to baseline one day after stimulus removal. Expression of ECM genes was greater in response to Angiotensin II and remained elevated longer after Angiotensin II removal, compared to Isoproterenol. Further, collagen content may be playing a role in the irreversible state of Angiotensin II induced hypertrophy as hydroxyproline content was increased following the removal of Angiotensin II in both males and females.\n\nConclusionsRegression of pathological cardiac hypertrophy is possible in some people and in some mouse models; however, the ability for the heart to regress is dependent on the stimulus and biological sex. Further, molecular changes including cellular signaling, protein degradation pathways and the formation of a fibrotic network may contribute to the ability to reverse pathological cardiac hypertrophy and are stimulus- and sex-dependent.\n\nTranslational PerspectivePathological cardiac hypertrophy is a major risk factor for mortality. If cardiac hypertrophy persists for an extended time, there can be many maladaptive changes to the myocardium. With early treatment of the underlying cause, cardiac hypertrophy can be reversed in some individuals, but not in others. While cardiac hypertrophy has been studied extensively, very little is understood about regression of cardiac hypertrophy. It is important that we have a better understanding of mechanisms leading to regression and why this process might not be reversible in some individuals.

molecular biology↗

bioRxiv2019

Cardiac contraction velocity has evolved to match heart rate with body size through variation in β-cardiac myosin sequence.

Heart rate and the maximum velocity of contraction of striated muscle are inversely related to species size. As mammals evolve to different sizes, adaptations are required such as slower contracting heart and skeletal muscles. Analysis of the motor domain of {beta}-myosin from 67 mammals from two clades identifies 14 sites, out of 800, strongly associated with body mass (p<0.01) but not with the clade (p>0.05). Nine of these sites were mutated in the human {beta}-myosin to make it resemble the rat sequence. Biochemical analysis revealed that the rat-human {beta}-myosin chimera functioned like the native rat myosin with a two fold increase in both motility and in the rate of ADP release from the actin.myosin cross-bridge (the step that limits contraction velocity). Both clades use the same small set of amino acids to adjust contraction velocity, suggesting a limited number of ways in which velocity can be manipulated.

biochemistry↗