Modeling Reduced Contractility and Stiffness Using iPSC-Derived Cardiomyocytes Generated From Female Becker Muscular Dystrophy Carrier

Kameda, Satoshi; Higo, Shuichiro; Shiba, Mikio; Kondo, Teruyuki; Li, Junjun; Liu, Li; Tabata, Tomoka; Inoue, Hiroyuki; Okuno, Shota; Ogawa, Shou; Kuramoto, Yuki; Yasutake, Hideki; Lee, Jong-Kook; Takashima, Seiji; Ikeda, Yoshihiko; Hikoso, Shungo; Miyagawa, Shigeru; Sakata, Yasushi

doi:10.1016/j.jacbts.2022.11.007

Cited by 3 publications

(6 citation statements)

References 58 publications

(80 reference statements)

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“…Rbm20 KO rodents and human iPSC-derived Rbm20 mutant cardiomyocytes show impaired cardiac contractility and myocardial stiffness, which is attributed to mis-splicing of calcium handling genes e.g., Ryr2 and Camk2d 72,73 , as well as impaired Frank-Starling mechanism due to mis-splicing of TTN (titin 54,74 ). These same pathophysiological features were recently documented in human iPSC-derived cardiomyocytes from a female Becker MD carrier engineered to have a DMD mutation 75 . While neither Rbm20 expression, nor its splicing targets, were investigated in the study by Kameda et al , the similarities in cardiac abnormalities between Rbm20-induced dilated cardiomyopathy and cardiomyopathy in female DMD carriers are evident and suggest that further research is warranted to ascertain the role of Rbm20 in female DMD carrier cardiomyopathy.…”

Section: Discussionsupporting

confidence: 70%

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Timpani,

Debrincat,

Kourakis

et al. 2024

Preprint

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Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates and citrate synthase activity but that these deficits can be offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggests that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.

show abstract

Section: Discussionsupporting

confidence: 70%

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Timpani,

Debrincat,

Kourakis

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…These same pathophysiological features were recently documented in human iPSC-derived cardiomyocytes from a female Becker MD carrier engineered to have a DMD mutation. 83 While neither Rbm20 expression, nor its splicing targets, were investigated in the study by Kameda et al, the similarities in cardiac abnormalities between Rbm20induced dilated cardiomyopathy and cardiomyopathy in female DMD carriers are evident and suggest that further research is warranted to ascertain the role of Rbm20 in female DMD carrier cardiomyopathy.…”

Section: Discussionmentioning

confidence: 98%

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock‐related protein Rbm20 in female mdx mice

Timpani,

Debrincat,

Kourakis

et al. 2024

The FASEB Journal

View full text Add to dashboard Cite

Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT‐labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates, and citrate synthase activity but that these deficits are offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA‐binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggest that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post‐menopausal DMD carriers.

show abstract

“…In summary, the study by Kameda et al 2 shows how a second hit in PLOD3 may contribute to reduced cardiac function and tissue stiffness in Δ45-48 DMD iPSC-CM tissues. Future understanding of the details in the interaction among PLOD3, collagen structure, and mechanotransduction through the dystrophin-glycoprotein complex to the contractile apparatus will help deepen understanding of the cardiomyocyte-ECM interaction.…”

mentioning

confidence: 85%

“…In this issue of JACC: Basic to Translational Science , Kameda et al 2 explore the pathogenesis of severe heart failure in a BMD carrier. They identify a second hit mutation in procollagen-lysine, 2-oxoglutarate 5 dioxygenase 3 (PLOD3) and demonstrate functional consequences in patient-derived induced pluripotent stem cell (iPSC) CM tissue rings.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tissue Rings PLOD Out a Second Hit in Becker Muscular Dystrophy

Lee

Margulies

2023

JACC: Basic to Translational Science

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Modeling Reduced Contractility and Stiffness Using iPSC-Derived Cardiomyocytes Generated From Female Becker Muscular Dystrophy Carrier

Cited by 3 publications

References 58 publications

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock‐related protein Rbm20 in female mdx mice

Tissue Rings PLOD Out a Second Hit in Becker Muscular Dystrophy

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