The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction

Research output: Contribution to journalArticle

Somik Chatterjee, Shumin Li, Aijun Zhang, Indira Vedula, Judy AlRukby,, Dale J. Hamilton, Anisha A. Gupte

Diastolic dysfunction (DD) is prevalent in elderly post-menopausal women. In addition to impaired cardiac relaxation and output, DD is associated with loss of skeletal muscle mass, muscle strength and function, and exercise capacity. Understanding the mechanisms of estrogen (E2)-mediated regulation of skeletal muscle structure and function in DD can have broader implications in understanding the progression of heart disease in post-menopausal women. In muscle, E2 regulates autophagy and mitophagy, processes that orchestrate degradation and recycling of damaged cellular components to maintain healthy tissue and conserve energy. However, this role of E2 under a physiological stress such as DD, is largely unknown. Our study aimed to understand the relationship between E2, autophagy/mitophagy and muscle function in DD. We hypothesized that estrogen receptor (ER) signaling plays a direct role in regulation of autophagy and mitophagy-mediated maintenance of muscle mass and muscle mitochondrial function in DD. Sham or ovariectomy (OVX) surgeries were performed to induce E2-deficiency, followed by induction of DD by administering hypertension agents L-NAME and angiotensin II. NMR analysis revealed significantly reduced total lean mass in OVX mice with DD, further confirmed by direct measurement of gastrocnemius muscle mass. Expression of ERα target-genes PDK4 and STAT3 were reduced in muscle of OVX mice with DD. DD significantly reduced LC3B II/I ratio in muscle, indicative of reduced autophagy. Consistent with this, expression of transcription factor FoxO3, a master-regulator of multiple autophagy and mitophagy genes, was reduced in OVX mice with DD compared to sham control mice. Expression of SDHA gene coding for mitochondrial respiratory chain subunit II, was reduced in sham and OVX mice with DD compared to sham control mice. Mitochondrial respiratory function measured from isolated muscle mitochondria, was reduced in sham and OVX mice with DD compared to sham control mice, and in OVX mice with DD compared to OVX control mice, indicating compromised skeletal muscle mitochondrial function. Our findings indicate that OVX-induced E2-deficiency and DD leads to muscle impairments, including defects in mitochondrial function.
Original languageEnglish (US)
JournalCirculation research
Volume125
StatePublished - Jul 29 2019

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The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction. / Chatterjee, Somik; Li, Shumin; Zhang, Aijun; Vedula, Indira; AlRukby, Judy; Hamilton, Dale J.; Gupte, Anisha A.

In: Circulation research, Vol. 125, 29.07.2019.

Research output: Contribution to journalArticle

Harvard

Chatterjee, S, Li, S, Zhang, A, Vedula, I, AlRukby, J, Hamilton, DJ & Gupte, AA 2019, 'The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction' Circulation research, vol. 125.

APA

Chatterjee, S., Li, S., Zhang, A., Vedula, I., AlRukby, J., Hamilton, D. J., & Gupte, A. A. (2019). The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction. Circulation research, 125.

Vancouver

Chatterjee S, Li S, Zhang A, Vedula I, AlRukby, J, Hamilton DJ et al. The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction. Circulation research. 2019 Jul 29;125.

Author

Chatterjee, Somik ; Li, Shumin ; Zhang, Aijun ; Vedula, Indira ; AlRukby, Judy ; Hamilton, Dale J. ; Gupte, Anisha A. / The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction. In: Circulation research. 2019 ; Vol. 125.

BibTeX

@article{1199e93181d64dc18eeaf19b0e9f5e7a,
title = "The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction",
abstract = "Diastolic dysfunction (DD) is prevalent in elderly post-menopausal women. In addition to impaired cardiac relaxation and output, DD is associated with loss of skeletal muscle mass, muscle strength and function, and exercise capacity. Understanding the mechanisms of estrogen (E2)-mediated regulation of skeletal muscle structure and function in DD can have broader implications in understanding the progression of heart disease in post-menopausal women. In muscle, E2 regulates autophagy and mitophagy, processes that orchestrate degradation and recycling of damaged cellular components to maintain healthy tissue and conserve energy. However, this role of E2 under a physiological stress such as DD, is largely unknown. Our study aimed to understand the relationship between E2, autophagy/mitophagy and muscle function in DD. We hypothesized that estrogen receptor (ER) signaling plays a direct role in regulation of autophagy and mitophagy-mediated maintenance of muscle mass and muscle mitochondrial function in DD. Sham or ovariectomy (OVX) surgeries were performed to induce E2-deficiency, followed by induction of DD by administering hypertension agents L-NAME and angiotensin II. NMR analysis revealed significantly reduced total lean mass in OVX mice with DD, further confirmed by direct measurement of gastrocnemius muscle mass. Expression of ERα target-genes PDK4 and STAT3 were reduced in muscle of OVX mice with DD. DD significantly reduced LC3B II/I ratio in muscle, indicative of reduced autophagy. Consistent with this, expression of transcription factor FoxO3, a master-regulator of multiple autophagy and mitophagy genes, was reduced in OVX mice with DD compared to sham control mice. Expression of SDHA gene coding for mitochondrial respiratory chain subunit II, was reduced in sham and OVX mice with DD compared to sham control mice. Mitochondrial respiratory function measured from isolated muscle mitochondria, was reduced in sham and OVX mice with DD compared to sham control mice, and in OVX mice with DD compared to OVX control mice, indicating compromised skeletal muscle mitochondrial function. Our findings indicate that OVX-induced E2-deficiency and DD leads to muscle impairments, including defects in mitochondrial function.",
author = "Somik Chatterjee and Shumin Li and Aijun Zhang and Indira Vedula and Judy AlRukby, and Hamilton, {Dale J.} and Gupte, {Anisha A.}",
year = "2019",
month = "7",
day = "29",
language = "English (US)",
volume = "125",
journal = "Circulation research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",

}

RIS

TY - JOUR

T1 - The Role of Estrogen in Protection of Skeletal Muscle Function in Diastolic Dysfunction

AU - Chatterjee, Somik

AU - Li, Shumin

AU - Zhang, Aijun

AU - Vedula, Indira

AU - AlRukby,, Judy

AU - Hamilton, Dale J.

AU - Gupte, Anisha A.

PY - 2019/7/29

Y1 - 2019/7/29

N2 - Diastolic dysfunction (DD) is prevalent in elderly post-menopausal women. In addition to impaired cardiac relaxation and output, DD is associated with loss of skeletal muscle mass, muscle strength and function, and exercise capacity. Understanding the mechanisms of estrogen (E2)-mediated regulation of skeletal muscle structure and function in DD can have broader implications in understanding the progression of heart disease in post-menopausal women. In muscle, E2 regulates autophagy and mitophagy, processes that orchestrate degradation and recycling of damaged cellular components to maintain healthy tissue and conserve energy. However, this role of E2 under a physiological stress such as DD, is largely unknown. Our study aimed to understand the relationship between E2, autophagy/mitophagy and muscle function in DD. We hypothesized that estrogen receptor (ER) signaling plays a direct role in regulation of autophagy and mitophagy-mediated maintenance of muscle mass and muscle mitochondrial function in DD. Sham or ovariectomy (OVX) surgeries were performed to induce E2-deficiency, followed by induction of DD by administering hypertension agents L-NAME and angiotensin II. NMR analysis revealed significantly reduced total lean mass in OVX mice with DD, further confirmed by direct measurement of gastrocnemius muscle mass. Expression of ERα target-genes PDK4 and STAT3 were reduced in muscle of OVX mice with DD. DD significantly reduced LC3B II/I ratio in muscle, indicative of reduced autophagy. Consistent with this, expression of transcription factor FoxO3, a master-regulator of multiple autophagy and mitophagy genes, was reduced in OVX mice with DD compared to sham control mice. Expression of SDHA gene coding for mitochondrial respiratory chain subunit II, was reduced in sham and OVX mice with DD compared to sham control mice. Mitochondrial respiratory function measured from isolated muscle mitochondria, was reduced in sham and OVX mice with DD compared to sham control mice, and in OVX mice with DD compared to OVX control mice, indicating compromised skeletal muscle mitochondrial function. Our findings indicate that OVX-induced E2-deficiency and DD leads to muscle impairments, including defects in mitochondrial function.

AB - Diastolic dysfunction (DD) is prevalent in elderly post-menopausal women. In addition to impaired cardiac relaxation and output, DD is associated with loss of skeletal muscle mass, muscle strength and function, and exercise capacity. Understanding the mechanisms of estrogen (E2)-mediated regulation of skeletal muscle structure and function in DD can have broader implications in understanding the progression of heart disease in post-menopausal women. In muscle, E2 regulates autophagy and mitophagy, processes that orchestrate degradation and recycling of damaged cellular components to maintain healthy tissue and conserve energy. However, this role of E2 under a physiological stress such as DD, is largely unknown. Our study aimed to understand the relationship between E2, autophagy/mitophagy and muscle function in DD. We hypothesized that estrogen receptor (ER) signaling plays a direct role in regulation of autophagy and mitophagy-mediated maintenance of muscle mass and muscle mitochondrial function in DD. Sham or ovariectomy (OVX) surgeries were performed to induce E2-deficiency, followed by induction of DD by administering hypertension agents L-NAME and angiotensin II. NMR analysis revealed significantly reduced total lean mass in OVX mice with DD, further confirmed by direct measurement of gastrocnemius muscle mass. Expression of ERα target-genes PDK4 and STAT3 were reduced in muscle of OVX mice with DD. DD significantly reduced LC3B II/I ratio in muscle, indicative of reduced autophagy. Consistent with this, expression of transcription factor FoxO3, a master-regulator of multiple autophagy and mitophagy genes, was reduced in OVX mice with DD compared to sham control mice. Expression of SDHA gene coding for mitochondrial respiratory chain subunit II, was reduced in sham and OVX mice with DD compared to sham control mice. Mitochondrial respiratory function measured from isolated muscle mitochondria, was reduced in sham and OVX mice with DD compared to sham control mice, and in OVX mice with DD compared to OVX control mice, indicating compromised skeletal muscle mitochondrial function. Our findings indicate that OVX-induced E2-deficiency and DD leads to muscle impairments, including defects in mitochondrial function.

M3 - Article

VL - 125

JO - Circulation research

T2 - Circulation research

JF - Circulation research

SN - 0009-7330

ER -

ID: 57001511