Aug 2026· Journal of Molecular and Cellular Cardiology· Vol 218, pp. 130-136· 0 citations· 15 references
Medicine
TL;DR
Using induced pluripotent stem cell-derived cardiomyocytes from a biallelic TTNtv patient with dilated cardiomyopathy, sarcomere structure/function is investigated and inefficient sarcomere assembly and interaction promotes cardiomyopathy in biallelic TTNtv.
Abstract
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.
The dystrophin–glycoprotein complex (DGC) is a structural and signaling network of cardiac muscle. It connects the extracellular matrix to the intracellular cytoskeleton. Dystroglycan, a component of the DGC, plays an essential role in maintaining the integrity of the sarcolemma of cardiac muscle. It contributes to sarcolemma stability, force transmission, mechanotransduction, calcium homeostasis, and cardiomyocyte survival. While the role of dystroglycan signaling is well established in many inherited disorders such as Duchenne muscular dystrophy, it is less studied in acquired heart failure with reduced ejection fraction (HFrEF). Emerging evidence suggests that dystroglycan remodeling may also occur in HFrEF. This review critically analyzes dystroglycan signaling in healthy and failing hearts, with particular emphasis on its emerging role in acquired HFrEF, including cardiac remodeling and fibrosis.
Unknown authors· International Journal of Mol...· 0 citations
Background Mutations in DSP, which encodes the protein desmoplakin, lead to cardiomyopathy with unusually high penetrance that presents with arrhythmias, fibro-fatty infiltration, and eventually heart failure. However, the precise mechanism of contractile dysfunction and dilation are incompletely understood. Here, we investigate the pathogenesis of DSP-R451G, a missense mutation that results in complete degradation of desmoplakin protein. Methods We use three complementary models to characterize desmoplakin-linked cardiomyopathy: iPSC-derived engineered heart tissue expressing R451G desmoplakin, a heterozygous DspWT/R451G knock-in mouse, and left-ventricular biopsy specimens. Tissue-engineered constructs are used to characterize contractility, calcium handling, sarcomere length, and cell signaling. These results are corroborated in the R451G mouse. To expand the generalizability of the findings, we compare them to those from human heart biopsies bearing three different desmoplakin mutations. Results Using iPSC-derived engineered heart tissue and isolated mouse ventricular cardiomyocytes, we recapitulate a disease phenotype consistent with desmoplakin cardiomyopathy and identify shortened resting sarcomere length as a pathogenic mechanism for contractile dysfunction. Phosphorylation of Src and protein kinase C underlie sarcomere shortening in mutant tissues and pharmacological inhibition of these kinases rescues sarcomere length. Notably, these sarcomeric and biochemical hallmarks are also present in human hearts bearing three different desmoplakin mutations. We next identify redistribution of mechanical force at cardiomyocyte junctions as a proximal factor that may promote mechanoactivation of Src. Finally, we rescue sarcomere length and contractile function in DSP-mutant engineered heart tissue with dasatinib, an FDA-approved receptor tyrosine kinase inhibitor. Conclusion Our study reveals a mechanism by which a desmosomal mutation affects cardiomyocyte function at the sarcomere level through activation of key signaling pathways that have not previously been implicated in desmoplakin cardiomyopathy.
Ilhan Gokhan, Maggie McKay, Xia Li et al.· Circulation Research· 0 citations
The Popeye domain-containing protein 1 (Popdc1, also known as Bves) is a transmembrane protein whose dysfunction is closely associated with various diseases. Clinical studies have identified that mutations in the bves gene predispose individuals to limb-girdle muscular dystrophy. However, a marked reduction in Bves protein expression has been observed in patients with heart failure, highlighting a critical unresolved challenge in understanding its role in disease pathogenesis. In this study, we discovered that bves deficiency drives cardiac contractile dysfunction, thereby revealing a novel mechanism underlying heart failure pathogenesis. The study found that bves knockout led to cardiac contractile dysfunction in zebrafish during both embryonic and adult stages, with a significant reduction in ejection fraction. Twelve-month-old bves knockout zebrafish exhibited ventricular dilation, increased cardiomyocyte size but significantly decreased cell numbers, and aggravated fibrosis of atrioventricular valves. Transmission electron microscopy revealed widened Z-lines and shortened I-bands in myocardial fibers of the bves knockout group. Collectively, these findings provide compelling evidence that bves knockout induces heart damage. Transcriptome analysis showed disrupted expression of ATP synthesis-related genes and activation of the mitochondrial autophagy pathway following bves knockout. In bves knockout zebrafish, myocardial mitochondria exhibited abnormal structure and impaired oxidative respiratory function, with upregulated expression levels of a series of protein complexes in the mitochondrial electron transport chain. These studies have for the first time established that myocardial mitochondrial structural/functional damage caused by bves deficiency may be associated with the pathogenesis of heart failure, providing a new perspective for the occurrence and development of heart failure.
Wanwan Cai, Wanbang Zhou, J. Lei et al.· Life Science· 0 citations
Hypertrophic cardiomyopathy (HCM) is a prototypical inherited cardiomyopathy with well-defined sarcomeric genetic underpinnings that make it an attractive target for molecular therapy. We review recent advances in gene-based approaches for HCM, including adeno-associated virus-mediate gene replacement, allele-specific silencing, and emerging gene editing strategies, and highlight the first demonstrations of in vivo target engagement and early clinical translation. Early-phase studies suggest that restoration of sarcomeric biology can favorably impact molecular and structural disease features. We further discuss key challenges related to immune responses, delivery efficiency, response durability, and patient selection that will shape the next phase of development. Together, these developments establish HCM as one of the important early models for cardiac gene therapy and highlight both the promise and complexity of translating genetic insight into durable clinical benefit.
Susan K. Keen, Barry Greenberg, M. Desai· i Medicina· 0 citations
Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are now widely applied in treatment plans for heart failure with reduced ejection fraction (HFrEF) patients, regardless of the presence of diabetes. SGLT2i, such as empagliflozin (EMP), reduce the risk of cardiovascular death and heart failure hospitalizations in HFrEF patients. However, the underlying molecular mechanisms of action, by which SGLT2i benefit cardiomyocytes (CMs) in HFrEF hearts, are not well understood. This study investigated the role of the SGLT2i, EMP, in a patient-specific human model of dilated cardiomyopathy (DCM), a primary cause of HFrEF, which is frequently caused by inherited mutations in sarcomere proteins. We employed DCM patient-specific induced pluripotent stem cell-derived CMs (iPSC-CMs) carrying the inherited sarcomere protein mutation tropomyosin (TPM1)-L185F together with high-speed motion traction and optical action potential mapping analysis, as well as biochemical methods to dissect molecular signaling dysfunctions. Our findings indicate that in DCM patient-specific iPSC-CMs, SGLT2i may act via different mechanisms. This includes the regulation of signaling pathways, to modulate sarcomere function via improving mitochondrial respiration and ATP production. As our results show, the SGLT2i, EMP, ameliorates primary sarcomere dysfunctions in DCM TPM1-L185F iPSC-CMs, such as disrupted sarcomere organization, reduced contractile function, and prolonged action potential duration. Moreover, we found that a subcellular signaling pathway dysregulated in DCM CMs, clathrin-mediated endocytosis (CME)-dependent signaling, may be recovered by EMP treatment in DCM TPM1-L185F iPSC-CMs. This pathway is essential for the uptake and distribution of critical cargo, such as transferrin-bound Fe, in CMs. In the presence of the DCM-causing mutation, EMP recovered mitochondrial Fe levels and mitochondrial functional output, which are reduced in DCM iPSC-CMs as part of pathologically defective CME-dependent signaling. These findings support that EMP modulates aspects of CME-signaling, and contributes to restored sarcomere functions. To further elucidate the effects of SGLT2i in DCM CMs, we investigated the molecular functions of a state-of-the-art combinatorial therapy for DCM (HFrEF) patients, the drug combination referred to as “fantastic four” (F4), including an SGLT2i, in DCM iPSC-CMs. Our in-vitro results point to a significant benefit of F4 to be attributed to the SGLT2i, EMP, regarding sarcomere functions as well as aspects of CME-dependent recovery of molecular signaling. Moreover, studying the recovery of subcellular dysfunctions by EMP treatment, findings from an in-vivo porcine model of HF support improvements observed in the presence of EMP regarding contractile and electrophysiological parameters. Together, our findings provide molecular insights into the subcellular function of SGLT2i and their role as part of the F4 state-of-the-art combination therapy for HFrEF, via targeting different molecular signaling pathways in a human patient-specific 2D model of HFrEF.
Daria Plota, H. N. Saleem, K. Lin et al.· Journal of Translational Med...· 0 citations
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