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

Timpani, CA; Debrincat, D; Kourakis, S; Boyer, R; Formosa, LE; Steele, JR; Zhang, H; Schittenhelm, RB; Russell, AP; Rybalka, E; Lindsay, A

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

Timpani, CA Debrincat, D Kourakis, S Boyer, R Formosa, LE Steele, JR Zhang, H Schittenhelm, RB Russell, AP Rybalka, E Lindsay, A

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Publisher:: WILEY
Publication Type:: Journal Article
Citation:: FASEB J, 2024, 38, (11), pp. e23718
Issue Date:: 2024-06-15

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Field	Value	Language
dc.contributor.author	Timpani, CA
dc.contributor.author	Debrincat, D
dc.contributor.author	Kourakis, S
dc.contributor.author	Boyer, R
dc.contributor.author	Formosa, LE
dc.contributor.author	Steele, JR
dc.contributor.author	Zhang, H
dc.contributor.author	Schittenhelm, RB
dc.contributor.author	Russell, AP
dc.contributor.author	Rybalka, E
dc.contributor.author	Lindsay, A
dc.date.accessioned	2025-05-11T05:16:23Z
dc.date.available	2024-05-19
dc.date.available	2025-05-11T05:16:23Z
dc.date.issued	2024-06-15
dc.identifier.citation	FASEB J, 2024, 38, (11), pp. e23718
dc.identifier.issn	0892-6638
dc.identifier.issn	1530-6860
dc.identifier.uri	http://hdl.handle.net/10453/187308
dc.description.abstract	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.
dc.format	Print
dc.language	eng
dc.publisher	WILEY
dc.relation.ispartof	FASEB J
dc.relation.isbasedon	10.1096/fj.202400329R
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 0606 Physiology, 1116 Medical Physiology
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3208 Medical physiology
dc.subject.mesh	Animals
dc.subject.mesh	Female
dc.subject.mesh	Mice
dc.subject.mesh	Estrogens
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Inbred mdx
dc.subject.mesh	Mitochondria
dc.subject.mesh	Mitochondria, Muscle
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Muscular Dystrophy, Duchenne
dc.subject.mesh	Ovariectomy
dc.subject.mesh	RNA-Binding Proteins
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Mitochondria
dc.subject.mesh	Mitochondria, Muscle
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Inbred mdx
dc.subject.mesh	Mice
dc.subject.mesh	Muscular Dystrophy, Duchenne
dc.subject.mesh	RNA-Binding Proteins
dc.subject.mesh	Estrogens
dc.subject.mesh	Ovariectomy
dc.subject.mesh	Female
dc.subject.mesh	Animals
dc.subject.mesh	Female
dc.subject.mesh	Mice
dc.subject.mesh	Estrogens
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Inbred mdx
dc.subject.mesh	Mitochondria
dc.subject.mesh	Mitochondria, Muscle
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Muscular Dystrophy, Duchenne
dc.subject.mesh	Ovariectomy
dc.subject.mesh	RNA-Binding Proteins
dc.title	Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in female mdx mice.
dc.type	Journal Article
utslib.citation.volume	38
utslib.location.activity	United States
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	0606 Physiology
utslib.for	1116 Medical Physiology
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Provost
pubs.organisational-group	University of Technology Sydney/Provost/Jumbunna
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-05-11T05:16:10Z
pubs.issue	11
pubs.publication-status	Published
pubs.volume	38
utslib.citation.issue	11

Abstract:

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.

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http://hdl.handle.net/10453/187308