Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathy

Parvatiyar, Michelle S.; Brownstein, Alexandra J.; Kanashiro‐Takeuchi, Rosemeire M.; Collado, Judd R.; Jones, Karissa M. Dieseldorff; Gopal, Jay; Hammond, Katherine G; Marshall, Jamie L.; Ferrel, Abel; Beedle, Aaron M.; Chamberlain, Jeffrey S.; Pinto, José R.; Crosbie, Rachelle H.

doi:10.1172/jci.insight.123855

Cited by 24 publications

(21 citation statements)

References 55 publications

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“…We have found that upregulation of sarcospan increases the α7β1D integrin complex, which has not been observed in mice overexpressing utrophin [34]. In addition to demonstrating that sarcospan overexpression improves skeletal and cardiac muscle function, we speculate that sarcospan overexpression has other beneficial effects and may act as a combinatorial therapy to boost existing therapies or therapies in development [24,25,39]. Recently, the group of Dr. Kay Davies found that transgenic utrophin overexpression, when used in combination with phosphonodiamidite morpholino antisense oligonucleotide to restore dystrophin, resulted in greater rescue than with exon skipping treatment alone [40].…”

Section: Discussionmentioning

confidence: 72%

High-throughput screening identifies modulators of sarcospan that stabilize muscle cells and exhibit activity in the mouse model of Duchenne muscular dystrophy

et al. 2020

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Background Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by mutations in the dystrophin gene. Loss of dystrophin prevents the formation of a critical connection between the muscle cell membrane and the extracellular matrix. Overexpression of sarcospan (SSPN) in the mouse model of DMD restores the membrane connection and reduces disease severity, making SSPN a promising therapeutic target for pharmacological upregulation. Methods Using a previously described cell-based promoter reporter assay of SSPN gene expression (hSSPN-EGFP), we conducted high-throughput screening on libraries of over 200,000 curated small molecules to identify SSPN modulators. The hits were validated in both hSSPN-EGFP and hSSPN-luciferase reporter cells. Hit selection was conducted on dystrophin-deficient mouse and human myotubes with assessments of (1) SSPN gene expression using quantitative PCR and (2) SSPN protein expression using immunoblotting and an ELISA. A membrane stability assay using osmotic shock was used to validate the functional effects of treatment followed by cell surface biotinylation to label cell surface proteins. Dystrophin-deficient mdx mice were treated with compound, and muscle was subjected to quantitative PCR to assess SSPN gene expression. Results We identified and validated lead compounds that increased SSPN gene and protein expression in dystrophin-deficient mouse and human muscle cells. The lead compound OT-9 increased cell membrane localization of compensatory laminin-binding adhesion complexes and improved membrane stability in DMD myotubes. We demonstrated that the membrane stabilizing benefit is dependent on SSPN. Intramuscular injection of OT-9 in the mouse model of DMD increased SSPN gene expression. Conclusions This study identifies a pharmacological approach to treat DMD and sets the path for the development of SSPN-based therapies.

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Section: Discussionmentioning

confidence: 72%

High-throughput screening identifies modulators of sarcospan that stabilize muscle cells and exhibit activity in the mouse model of Duchenne muscular dystrophy

et al. 2020

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“…Cardiac function [EF, cardiac output (CO), and stroke volume (SV)] were calculated using Vevo-2100 imaging system (Visual Sonics Inc.) at baseline, 1-, 4- and 8-week post-MI as previously described with minor modifications [ 23 , 24 ] . Briefly, mice were anesthetized by inhalation with 1%-3% isoflurane while heart rates and body temperatures were continuously monitored.…”

Section: Methodsmentioning

confidence: 99%

“…Pressure-volume data were obtained from steady-state and inferior vena cava occlusion using a Power Lab data acquisition system (ADInstruments, Denver, CO) as previously described [ 23 , 24 ] . A microtip pressure-volume catheter (SPR 839, Millar Instruments) was introduced into the surgically exposed right carotid artery and advanced into the left ventricle.…”

Section: Methodsmentioning

confidence: 99%

Systemic delivery of large-scale manufactured Wharton’s Jelly mesenchymal stem cell-derived extracellular vesicles improves cardiac function after myocardial infarction

Bellio¹,

Kanashiro‐Takeuchi²,

Takeuchi³

et al. 2022

JCA

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Introduction: Cardiovascular disease and myocardial infarction are leading causes of morbidity and mortality in aged populations. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are under evaluation as a therapeutic option for the treatment of myocardial infarction. Aim: This study aimed to develop a large-scale manufacturing procedure to harvest clinical-grade EVs required for the translation of EVs to the clinic. Methods and Results: We compared the efficiency of large scale MSC-derived EV production and characterized EV miRNA cargo using the Quantum bioreactor with either fetal bovine serum or human platelet lysate (PLT)-containing expansion media. We tested the potency of the EV products in a murine model of acute myocardial infarction. Our results demonstrate an advantage of the Quantum bioreactor as a large-scale platform for EV production using PLT media; however, both media produced EVs with similar effects in vivo. The systemic delivery of EV products improved cardiac function following myocardial infarctions as indicated by a significant improvement in ejection fraction as well as parameters of cardiac performance, afterload, contractility and lusitropy. Conclusion: These findings have important implications for scale-up strategies of EVs and will facilitate clinical trials for their clinical evaluation.

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“…Echocardiography and analysis were performed using a Vevo 2100 high‐resolution in vivo imaging system and workstation as described previously (Dieseldorff Jones et al, 2019; Parvatiyar et al, 2019). Three‐month‐old male and female mice of both genotypes were maintained under light anesthesia with isoflurane (∼2%) during the procedure.…”

Section: Methodsmentioning

confidence: 99%

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

et al. 2020

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Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants in both sexes. Among the susceptible genes, TNNC1—encoding cardiac troponin C (cTnC)—causes a substantial HCM phenotype in mice. Mice bearing an HCM‐associated cTnC‐A8V point mutation exhibited a significant decrease in stroke volume and left ventricular diameter and volume. Importantly, isovolumetric contraction time was significantly higher for female HCM mice. We utilized a transcriptomic approach to investigate the basis underlying the sexual dimorphism observed in the cardiac physiology of adult male and female HCM mice. RNA sequencing revealed several altered canonical pathways within the HCM mice versus WT groups including an increase in eukaryotic initiation factor 2 signaling, integrin‐linked kinase signaling, actin nucleation by actin‐related protein‐Wiskott‐Aldrich syndrome family protein complex, regulation of actin‐based motility by Rho kinase, vitamin D receptor/retinoid X receptor activation, and glutathione redox reaction pathways. In contrast, valine degradation, tricarboxylic acid cycle II, methionine degradation, and inositol phosphate compound pathways were notably down‐regulated in HCM mice. These down‐regulated pathways may be reduced in response to altered energetics in the hypertrophied hearts and may represent conservation of energy as the heart is compensating to meet increased contractile demands. HCM male versus female mice followed similar trends of the canonical pathways altered between HCM and WT. In addition, seven of the differentially expressed genes in both WT and HCM male versus female comparisons swapped directions in fold‐change between the sexes. These findings suggest a sexually‐dimorphic HCM phenotype due to a sarcomeric mutation and pinpoint several key targetable pathways and genes that may provide the means to alleviate the more severe decline in female cardiac function.

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Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathy

Cited by 24 publications

References 55 publications

High-throughput screening identifies modulators of sarcospan that stabilize muscle cells and exhibit activity in the mouse model of Duchenne muscular dystrophy

High-throughput screening identifies modulators of sarcospan that stabilize muscle cells and exhibit activity in the mouse model of Duchenne muscular dystrophy

Systemic delivery of large-scale manufactured Wharton’s Jelly mesenchymal stem cell-derived extracellular vesicles improves cardiac function after myocardial infarction

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

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