TY - JOUR
T1 - Age and ischemia differentially impact mitochondrial ultrastructure and function in a novel model of age-associated estrogen deficiency in the female rat heart
AU - Garvin, Alexandra M.
AU - Aurigemma, Nicole C.
AU - Hackenberger, Jenna L.
AU - Korzick, Donna H.
N1 - Funding Information:
The authors acknowledge the TEM analysis provided by Jessica Henry. This article is part of the Topical Collection on Muscle Physiology All animal experimentation described was conducted with approval from the Institutional Animal Care and Use Committee of the Pennsylvania State University. The authors declare that they have no conflict of interest. National Heart, Lung, and Blood Institute [HL091097 to DHK]. National Institute on Aging [AG044132 to AMG, DHK]. Biological Seed Grant mechanism from the College of Health and Human Development and Huck Institutes of the Life Sciences [001 to DHK], Pennsylvania State University.
Funding Information:
Biological Seed Grant mechanism from the College of Health and Human Development and Huck Institutes of the Life Sciences [001 to DHK], Pennsylvania State University.
Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Altered mitochondrial respiration, morphology, and quality control collectively contribute to mitochondrial dysfunction in the aged heart. Because myocardial infarction remains the leading cause of death in aged women, the present study utilized a novel rodent model to recapitulate human menopause to interrogate the combination of age and estrogen deficiency on mitochondrial ultrastructure and function with cardiac ischemia/reperfusion (I/R) injury. Female F344 rats were ovariectomized (OVX) at 15 months and studied at 24 months (MO OVX; n = 40) vs adult ovary intact (6 months; n = 41). Temporal declines in estrogen concomitant with increased visceral adipose tissue were observed in MO OVX vs adult. Following in vivo coronary artery ligation or sham surgery, state 3 mitochondrial respiration was selectively reduced by age in subsarcolemmal mitochondria (SSM) and by I/R in interfibrillar mitochondria (IFM); left ventricular maximum dP/dt was reduced in MO OVX (p < 0.05). Elevated cyclophilin D and exacerbated I/R-induced mitochondrial acetylation in MO OVX suggest permeability transition pore involvement and reduced protection vs adult (p < 0.05). Mitochondrial morphology by TEM revealed an altered time course of autophagy coordinate with attenuated Drp1 and LC3BII protein levels with age-associated estrogen loss (p < 0.05). Here, reductions in both SSM and IFM function may play an additive role in enhanced susceptibility to regional I/R injury in aged estrogen-deficient female hearts. Moreover, novel insight into altered cardiac mitochondrial quality control garnered here begins to unravel the potentially important regulatory role of mitochondrial dynamics on sustaining respiratory function in the aged female heart.
AB - Altered mitochondrial respiration, morphology, and quality control collectively contribute to mitochondrial dysfunction in the aged heart. Because myocardial infarction remains the leading cause of death in aged women, the present study utilized a novel rodent model to recapitulate human menopause to interrogate the combination of age and estrogen deficiency on mitochondrial ultrastructure and function with cardiac ischemia/reperfusion (I/R) injury. Female F344 rats were ovariectomized (OVX) at 15 months and studied at 24 months (MO OVX; n = 40) vs adult ovary intact (6 months; n = 41). Temporal declines in estrogen concomitant with increased visceral adipose tissue were observed in MO OVX vs adult. Following in vivo coronary artery ligation or sham surgery, state 3 mitochondrial respiration was selectively reduced by age in subsarcolemmal mitochondria (SSM) and by I/R in interfibrillar mitochondria (IFM); left ventricular maximum dP/dt was reduced in MO OVX (p < 0.05). Elevated cyclophilin D and exacerbated I/R-induced mitochondrial acetylation in MO OVX suggest permeability transition pore involvement and reduced protection vs adult (p < 0.05). Mitochondrial morphology by TEM revealed an altered time course of autophagy coordinate with attenuated Drp1 and LC3BII protein levels with age-associated estrogen loss (p < 0.05). Here, reductions in both SSM and IFM function may play an additive role in enhanced susceptibility to regional I/R injury in aged estrogen-deficient female hearts. Moreover, novel insight into altered cardiac mitochondrial quality control garnered here begins to unravel the potentially important regulatory role of mitochondrial dynamics on sustaining respiratory function in the aged female heart.
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U2 - 10.1007/s00424-017-2034-7
DO - 10.1007/s00424-017-2034-7
M3 - Article
C2 - 28776263
AN - SCOPUS:85026836387
VL - 469
SP - 1591
EP - 1602
JO - Pflugers Archiv European Journal of Physiology
JF - Pflugers Archiv European Journal of Physiology
SN - 0031-6768
IS - 12
ER -