Biology subjects

Goergen, C. J.

Publications and source records attributed to Goergen, C. J..

14 recordsLinked to original sources

bioRxiv2026

Adaptations of the pregnant murine heart to pre-existing hypertension

2-5% of pregnancies are complicated by chronic hypertension [1], increasing the risk of peripartum cardiomyopathy and maternal morbidity [2, 3]. Hypertension reduces stroke volume, whereas pregnancy increases stroke volume. The combined impact of these opposing loads on cardiac function and strain remains unclear. We used a mouse model of pregnancy with pre-existing hypertension to characterize cardiac remodeling. We hypothesized that pregnancy may counteract hypertension-related reductions in cardiac function. Nulliparous female C57Bl6/J mice (7-11 weeks old) were assigned into pregnant (PREG, n=11), angiotensin II-treated (ANGII, n=7), and ANGII+PREG (n=8) groups. Hypertension was induced with subcutaneous angII infusion (1000 ng/kg/min). Cardiac function was measured with high-frequency ultrasound. Ejection fraction (EF) was maintained in PREG animals at 65% but decreased significantly by day 36 in ANGII animals (44.85{+/-}3.27%). In ANGII+PREG mice, EF initially decreased but trended towards PREG values on postpartum day 1. Left ventricle strain was lower in ANGII and ANGII+PREG groups compared to PREG. ANGII and ANGII+PREG animals showed decreased early longitudinal diastolic strain rate at mid-pregnancy compared to baseline (0.82{+/-}0.09% ANGII; 0.73{+/-}0.09% ANGII+PREG), while increasing in PREG (1.76{+/-}0.14%). Minimal physiologically relevant fibrosis was noted across groups via immunohistochemistry. Heart mass-to-body mass was lowest in PREG (6.20{+/-}0.22 mg/g), greatest in ANGII (8.95{+/-}0.39 mg/g), and intermediate in ANGII+PREG (6.92{+/-}0.25 mg/g). Cardiomyocyte cross-sectional area was similar between groups. Overall, pregnancy altered the functional and hypertrophic response to elevated blood pressure. Findings from this work set the foundation for future efforts that may eventually improve cardiovascular care for pregnant patients.

bioengineering↗

bioRxiv2026

Empagliflozin preserves cardiac function and modulates metabolism in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by skeletal muscle degeneration and cardiomyopathy without a cure. This study examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) on cardiac function in the dystrophin-deficient mdx mouse model of DMD. Male mice were fed control chow or EMPA-containing chow ([~]25 mg/kg/day), and cardiac function was evaluated longitudinally by four-dimensional ultrasound imaging. EMPA did not alter left ventricular mass or chamber volume but preserved ejection fraction (EF) for 12 weeks, maintained significantly higher EF through 24 weeks, and attenuated global impairment of systolic and diastolic myocardial deformation. These functional improvements were accompanied by reduced cardiomyocyte hypertrophy and decreased expression of cardiac stress genes. EMPA reduced mitochondrial DNA damage, increased mitochondrial DNA copy number, and induced transcriptional signatures consistent with enhanced fatty acid and ketone metabolism, contributing to increased myocardial ATP content. Systemically, EMPA improved body mass trajectory, preserved relative lean mass, enhanced skeletal muscle torque, and did not adversely affect renal function. Together, these findings demonstrate that EMPA improves cardiac performance and mitochondrial integrity while enhancing myocardial energy availability in mdx mice, supporting SGLT2 inhibitors as a promising therapeutic strategy for individuals with DMD.

physiology↗

bioRxiv2026

Positive allosteric modulator of SERCA pump NDC-1171 attenuates cardiac functional decline in mouse model of Duchenne muscular dystrophy

Progressive cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Dysregulation of calcium handling has been implicated in cardiomyopathy progression in DMD. Here we describe a therapeutic approach to improve calcium homeostasis in a mouse model of DMD using the novel therapeutic NDC-1171, which is a positive allosteric modulator of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump. We synthesized NDC-1171 and treated 4-week-old D2.mdx mice (n=9) via oral gavage. A group of D2.mdx mice (n=9) and a group of DBA/2J mice (n=9; background strain) received a vehicle on the same schedule. We used ultrasound to assess left ventricular function, followed by a treadmill exhaustion test and a 4-paw grip strength test to assess skeletal muscle function. NDC-1171 attenuated cardiac functional decline in D2.mdx mice. At 16 weeks of age, left ventricular ejection fraction (LVEF) was significantly preserved in mice treated with NDC-1171 (57.7{square}{+/-}{square}0.5%) compared to mice treated with a vehicle (50.7{square}{+/-}{square}0.9%, p{square}<{square}0.05), though remained lower than background strain controls (62.4{square}{+/-}{square}0.6%). In contrast, functional behavior testing revealed no significant improvement in skeletal muscle function with treatment. These data suggest that treatment with the SERCA pump modulator NDC-1171 helps preserve cardiac function in a murine model of DMD, even as skeletal muscle function was impaired. Future work will be needed to determine if the benefits of this novel SERCA activator translate to large animal and clinical studies, but these initial results are promising and could help guide development of future treatments for pediatric patients with muscular dystrophy.

pharmacology and toxicology↗

bioRxiv2026

Ultrasound-Based Hemodynamic Force Trajectories in a Murine Model of Reversible Pressure Overload

Hemodynamic forces (HDF) quantify intraventricular pressure gradients as integrated vectors derived from myocardial motion and blood flow, providing a sensitive marker of left ventricular pump efficiency beyond conventional metrics such as ejection fraction or strain. Although HDF analysis has been clinically validated in heart failure, it remains underexplored in preclinical models. To determine whether HDF metrics derived from high-resolution murine echocardiography can sensitively track cardiac dysfunction and predict functional recovery, male mice (n = 8) underwent serial echocardiography at baseline, after transverse aortic constriction (TAC), and four weeks after aortic debanding (deTAC). Left ventricular function and interval-specific HDF components were quantified, including longitudinal and transverse forces over predefined systolic and diastolic windows. Longitudinal interval-based parameters emerged as sensitive, integrative markers of LV dysfunction after TAC and DeTAC. Notably, a novel systolic acceleration-to-relaxation longitudinal HDF ratio showed the strongest associations with pressure overload and subsequent functional recovery (baseline vs TAC: p < 0.001; TAC vs deTAC: p < 0.001; baseline vs deTAC: p = 0.043). In contrast, diastolic HDF indices, including the previously proposed longitudinal e-wave ratio, did not significantly differentiate between time points. Transverse HDF over the systolic impulse interval further demonstrated potential for predicting post-surgical recovery following unloading. These findings support systolic HDF metrics, particularly longitudinal and transverse interval-based parameters, as sensitive integrative markers of LV dysfunction and reverse remodeling in preclinical pressure-overload models, and highlight their translational relevance for echocardiography-based HDF analysis. Key pointsHemodynamic force (HDF) analysis evaluate intraventricular pressure gradients as integrated vectors of myocardial motion and blood flow, providing complementary markers of pump (in)efficiency beyond ejection fraction or strain. High-resolution murine echocardiography enables robust derivation of interval-specific HDF metrics. Systolic HDF metrics, particularly transverse components during impulse intervals showed potential for predicting recovery. Systolic HDF reflect key changes in force generation and intraventricular flow during pressure overload, allowing early detection of maladaptive remodeling and treatment response, with strong translational potential for non-invasive risk stratification in aortic stenosis patients.

physiology↗

bioRxiv2025

Bayesian Inference Framework to Identify Skin Material Properties \textit{in vivo} from Active Membranes

Accurate in vivo characterization of skin mechanical properties is essential for diagnostics and treatment planning across dermatological and surgical applications. Existing noninvasive techniques are limited in capturing the nonlinear and anisotropic behavior of skin. In this work, we propose a Bayesian inference framework that leverages active membranes to induce desired deformations and infer patient-specific skin properties from a measured strain field. A finite element model of skin-membrane interaction, parameterized using the Holzapfel-Gasser-Ogden model, is used to generate strain field data under various membrane actuation conditions. To overcome the computational cost of repeated simulations required for Bayesian sampling, we construct a data-driven surrogate using principal component analysis for dimensionality reduction and Gaussian process regression for rapid evaluation. Our approach enables probabilistic inference of key skin parameters, including shear modulus, fiber stiffness, dispersion, and orientation. An advatange of the proposed method is that inference of skin biomechanics does not require direct force measurements. Rather, the method relies on known properties of active membranes (which can be tested ahead of time). The method does require strain field measurements. Through synthetic studies, we demonstrate that our method accurately recovers most model parameters even under moderate levels of spatially correlated noise, and that multi-frame or multi-membrane observations significantly enhance identifiability. These results establish the potential of active membranes as a viable platform for noninvasive, in vivo skin biomechanics assessment.

biophysics↗

bioRxiv2025

Murine Abdominal Aortic Aneurysm Intraluminal Thrombus Composition and Structure

An abdominal aortic aneurysm (AAA) is a dilation of the aortic wall in the abdomen. Many AAA patients develop intraluminal thrombus (ILT), but the role of ILT in AAA progression and rupture is not well understood. To evaluate ILT in AAAs, we induced AAAs in male C57Bl6/J mice (n=25) via surgical application of topical elastase (5 {micro}L of 5 or 10 mg/mL) to the abdominal aorta below the renal arteries and administration of {beta}-aminopropionitrile (BAPN, 0.2%) drinking water. We collected weekly/biweekly ultrasound images over 56 days. Mice were euthanized and histology images were collected. We semi-quantitatively assessed elastin degradation and inflammation from Movats pentachrome and H&E-stained samples, respectively. Mice with ILT had more significant expansion over the length of the study (beginning at day 14, p<0.05). From histology, ILT samples showed more elastin disorganization and greater inflammation. From scanning electron microscopy, we were able to confirm the presence of layered sheets of fibrin and abnormally shaped red blood cells (polyhedrocytes) within the ILT deposits. In this model, elastase causes aortic injury by degrading elastin fibrils in the aortic wall, reducing the ability of the aorta to contract during high-pressure blood flow. Further damage to the extracellular matrix is likely driven by subsequent inflammation. Here we observed tissue samples with greater acute-on-chronic inflammation were correlated with more elastin damage, and therefore greater aortic expansion. Further, larger aortic expansions were correlated with slower blood flow, likely due to increased cross-sectional area. Thus, increased aortic expansion and damage to the aortic wall may be more likely to create hemodynamic conditions that are conducive to the initiation of ILT deposition: endothelial damage and reduced blood flow. Understanding the relationship between ILT formation, aortic wall degradation, and inflammation could help refine therapeutic strategies for treating AAAs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/685150v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@f6ba71org.highwire.dtl.DTLVardef@4a8379org.highwire.dtl.DTLVardef@1fd97c1org.highwire.dtl.DTLVardef@1f60400_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Simplified and refined murine model of reversible aortic constriction for characterizing cardiac functional recovery

BackgroundHeart failure with reduced ejection fraction (HFrEF) is a major clinical issue with a poor prognosis. Structural and functional recovery, known as "reverse remodeling (RR)," has been observed in subsets of patients who respond favorably to treatment. However, progress in understanding the mechanisms behind RR has been hindered by a lack of animal models that accurately replicate this complex process. ObjectivesWe introduced a convenient and reproducible modification to the widely used transaortic constriction (TAC) procedure that allows for refined, timed, and noninvasive aortic de-banding (de-TAC), and functional recovery. MethodsA modified and releasable knot was used for an initial aortic constriction. Suture ends were left accessible from underneath the skin layer following the TAC surgery. After three weeks, deTAC was performed by re-opening in the skin layer and pulling on the suture to release the constriction. We assessed cardiac function, strain, and geometry with 2D and 4D ultrasound at baseline, 3 weeks after TAC, 1 week- and 4 weeks after deTAC. Tissue remodeling and cellular infiltration was characterized by quantifying fibrosis and fibroblast numbers via immunofluorescence. ResultsUltrasound revealed that aortic de-banding was associated with both functional and mechanical recovery. Cardiac function and strain decreased due to pressure overload, exhibiting characteristics of systolic dysfunction, but recovered to near baseline values by 1 week after deTAC. However, left ventricular mass, fibrosis and fibroblast numbers remained elevated, despite functional recovery. ConclusionThis simplified and refined TAC-based model of RR significantly facilitates and enhances research on cardiac remodeling and recovery. CONDENSED ABSTRACTA subset of heart failure patients (HF) respond favorably to treatment, displaying functional recovery via a process known as reverse remodeling (RR). Developing RR models will be key to characterizing currently elusive mechanisms driving this process and ultimately identifying potential therapeutic targets. Transverse aortic constriction (TAC) in rodents increases the afterload on the LV and is a common model of heart failure due to pressure overload. Here, we report a convenient and reproducible method that allows for precisely timed and surgery-free removal of aortic constriction (de-TAC). When performed 3-weeks after TAC, de-TAC produced significant cardiac functional recovery, with normalization of ejection fraction and strain assessed by 2D and 4D echocardiography, respectively. However, signs of adverse myocardial remodeling persisted, including hypertrophy, fibrosis, and elevated fibroblast numbers. In the relatively young field of cardiac RR, our method could facilitate investigations of functional, structural, cellular, and molecular changes underlying recovery from HF. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/646758v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@7b0d62org.highwire.dtl.DTLVardef@abc428org.highwire.dtl.DTLVardef@db2fe0org.highwire.dtl.DTLVardef@243950_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIAdaptation to the widely used transverse aortic constriction (TAC) procedure allows for minimally invasive de-TAC for studying reverse remodeling. C_LIO_LIThis model increases feasibility and reproducibility, with no requirement for additional instruments or materials. C_LIO_LIState-of the art 4DUS assessment of cardiac function, mechanics, and geometry shows extensive left-ventricular remodeling and significant recovery of function following de-TAC. C_LIO_LICardiac fibrosis is persistent following functional recovery from heart failure with reduced ejection fraction (HFrEF). C_LI

pathology↗

bioRxiv2024

Left Atrial Strain as a Predictor of Cardiac Dysfunction in a Murine Model of Pressure Overload

AimLeft atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis. MethodsHigh resolution ultrasound was performed in a cohort of mice (n=16) to evaluate left atrial and left ventricular function at baseline and 2- and 4-weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n=10) with 3-days post TAC imaging. ResultsWe report an increase in LA max volume from 11.0 {+/-} 4.3{micro}L at baseline to 26.7 {+/-} 16.7{micro}L at 4 weeks (p=0.002) and a decrease in LA strain from 19.6 {+/-} 4.8% at baseline to 10.1 {+/-} 6.3% at 4 weeks (p=0.006). In the acute phase, LA strain dysfunction was present at 3-days (p<0.001) prior to alterations in LA volume (p=0.856) or left ventricular (LV) ejection fraction (p=0.120). LA strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r=0.563, p<0.001), longitudinal strain (r=-0.643, p<0.001) and strain rate (r=0.387, p=0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC=0.858, p<0.001), ejection fraction (AUC=0.901 p<0.001), and strain (AUC=0.878, p<0.001) all predicted LV dysfunction. ConclusionLA strain and function assessments provide a reliable, non-invasive method for early detection and prediction of cardiac dysfunction in a model of pressure overload.

physiology↗

bioRxiv2024

OPA1 mediates cardiac function and metabolism: in silico and in vivo evidence

OPA1 is an inner mitochondrial membrane protein that mediates diverse signaling processes. OPA1 is important for cardiac function and protects against cardiac insults such as ischemia reperfusion injury. We sought to further assess OPA1 in human and mouse cardiac pathologies, hypothesizing that OPA1 may also function in a protective manner in chronic heart failure. Bioinformatic analyses of histological and transcript data from the GTEx database indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were correlated with fatty acid, branch chain amino acid and contractile gene signatures. To experimentally assess these correlations, mice with a 1.5-fold whole body OPA1 overexpression (OPA1-OE) were subjected to transverse aortic constriction surgery and displayed improved 2D and 4D cardiac functional parameters compared to WT mice. OPA1-OE mice had no induction of fibrotic transcript markers and displayed sustained transcript levels of fatty acid, branch chain amino acid and contractile markers. Maximal oxidative capacity was sustained in both WT and OPA1-OE cardiac myofibers post-TAC. These results further demonstrate the important role of OPA1 in mediating cardiac function and highlight protective signaling pathways.

biochemistry↗

bioRxiv2024

Functional cardiac consequences of β-adrenergic stress-induced injury in the mdx mouse model of Duchenne muscular dystrophy

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to enhance the cardiac phenotype in the mdx model, many methods lead to high mortality, variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. For our study, mdx and wild-type (WT) mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathologic assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels, and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes, and diminished cardiac reserve in mdx mice compared to wild-type. Our findings highlight the utility of low-dose isoproterenol in mdx mice as a valuable model for exploring therapies targeting DMD-associated cardiac complications. SUMMARY STATEMENTThis work introduces an improved method to model heart failure in mouse models of Duchenne muscular dystrophy and comprehensively describes underlying cellular and physiologic mechanisms using advanced imaging techniques.

physiology↗

bioRxiv2023

Deep learning enables accurate soft tissue deformation estimation in vivo

Image-based deformation estimation is an important tool used in a variety of engineering problems, including crack propagation, fracture, and fatigue failure. These tools have been instrumental in biomechanics research where measuring in vitro and in vivo tissue deformations help evaluate tissue health and disease progression. However, accurately measuring tissue deformation in vivo is particularly challenging due to limited image signal-to-noise ratio. Therefore, we created a novel deep-learning approach for measuring deformation from a sequence of in vivo images called StrainNet. Utilizing a training dataset that incorporates image artifacts, StrainNet was designed to maximize performance in challenging in vivo settings. Artificially generated image sequences of human flexor tendons undergoing known deformations were used to compare StrainNet against two conventional image-based strain measurement techniques. StrainNet outperformed the traditional techniques by nearly 90%. High-frequency ultrasound imaging was then used to acquire images of the flexor tendons engaged during contraction. Only StrainNet was able to track tissue deformations under the in vivo test conditions. Findings revealed strong correlations between tendon deformation and contraction effort, highlighting the potential for StrainNet to be a valuable tool for assessing preventative care, rehabilitation strategies, or disease progression. Additionally, by using real-world data to train our model, StrainNet was able to generalize and reveal important relationships between the effort exerted by the participant and tendon mechanics. Overall, StrainNet demonstrated the effectiveness of using deep learning for image-based strain analysis in vivo.

bioengineering↗

bioRxiv2023

Longitudinal Investigation of Aortic Dissection in Mice with Computational Fluid Dynamics

Patients with aortic dissection require lifelong surveillance to monitor disease progression and detect late adverse events such as aneurysmal dilation, malperfusion or refractory pain. The variety and complexity of aortic dissection have so far eluded definitive predictions of occurrence and timing of late adverse events. The search for early indicators of late adverse events has been based mostly on morphologic features, and one commonly observed risk factor is partial thrombosis of the false lumen. While the effect of partial thrombosis on disease progression is incompletely understood, hemodynamic factors, including low velocity or stagnant flow, are likely to play a role. In this study we investigated the progression of false lumen intramural thrombus formation in four mice with angiotensin IIinduced aortic dissection. Based on 3D B-mode ultrasound images, we created segmentations of the diseased aorta including the true lumen, false lumen, and thrombus. These geometries were then used to run computational fluid dynamic simulations with subject-specific boundary conditions. Each mouse was followed for seven days and 4-5 longitudinal image datasets were acquired for each animal. We found that false lumina with a single entry tear tend to have smaller mean relative velocities, and at the same time are subject to a larger false lumen thrombus ratio. Likewise, regions of low velocity correlated with regions of elevated endothelial cell activation potential and higher particle residence times. These findings support the hypothesis that flow stagnation is the predominant hemodynamic factor that results in a large thrombus ratio in false lumina, particularly those with a single entry tear. Additional work will be needed to further explore the intricacies of these complex experimental vascular lesions and how the hemodynamic conditions compare to human aortic dissections.

bioengineering↗

bioRxiv2023

Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation

BackgroundAtrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility. MethodsRight atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation. In vitro studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies. ResultsIn human patients with AF, PPP1R12C expression was increased two-fold versus SR controls (P=2.0x10-2, n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation (P=1.4x10-6, n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9x10-2 and 6.7x10-3 respectively, n=8,8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls (P=5.0x10-6, n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls (P=1.8x10-2 and 4.1x10-2 respectively, n= 6,6,5). ConclusionsAF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

molecular biology↗

bioRxiv2018

The Nucleus Mediates Mechanosensitive Reorganization of Epigenetically Marked Chromatin During Cardiac Maturation and Pathology

Environmental mechanical cues are critical to guide cell fate. Forces transmit to the nucleus through the Linker of Nucleo- and Cytoskeleton (LINC) complex and are thought to influence the organization of chromatin that is related to cell differentiation; however, the underlying mechanisms are unclear. Here, we investigated chromatin reorganization during murine cardiac development and found that cardiomyocytes establish a distinct architecture characterized by relocation of H3K9me3-modified chromatin from the nuclear interior to the periphery and co-localization to myofibrils. This effect was abrogated in stiff environments that inhibited cardiomyocyte contractility, or after LINC complex disruption, and resulted in the relocation of H3K27me3-modified chromatin instead. By generating high-resolution intra-nuclear strain maps during cardiomyocyte contraction, we discovered that the reorganization of H3K9me3-marked chromatin is influenced by tensile, but not compressive, nuclear strains. Our findings highlight a new role for nuclear mechanosensation in guiding cell fate through chromatin reorganization in response to environmental cues.

cell biology↗