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Cited by 57Mitochondrial Function and PathologyBirth, Development, and HealthCongenital heart defects research

Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms

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Larsen, Tricia D., Sabey, Kyle H., Knutson, Alexis J., Gandy, Tyler C. T., Louwagie, Eli J., Lauterboeck, Lothar, Mdaki, Kennedy S., Baack, Michelle L.·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20123090PMC PMC6627740
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Abstract

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role. Using confocal live-cell imaging, we examined mitochondrial dynamics in neonatal rat cardiomyocytes (NRCM) from four prenatally exposed groups: controls, diabetes, high-fat diet, and combination exposed. Cardiac expression of dynamism-related genes and proteins were compared, and gender-specific differences were evaluated. Findings show that normal NRCM have highly dynamic mitochondria with a well-balanced number of fusion and fission events. Prenatal exposure to diabetes or a high-fat diet impaired dynamism resulting in shorter, wider mitochondria. Mechanisms of impaired dynamism were gender-specific and protein regulated. Females had higher expression of fusion proteins which may confer a cardioprotective effect. Prenatally exposed male hearts had post-translational modifications known to impair dynamism and influence mitophagy-mediated cell death. This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels.

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  • The lack of effect of maternal diabetes on mitochondrial dynamics in female offspring cardiomyocytes is likely a consequence of higher protein expression of Mitofusin-2 and OPA1 that could protect against mitophagy-mediated cell death.

    “Notably, mitochondrial dynamics in cardiomyocytes from the female offspring were not affected by exposure to maternal diabetes, likely as a consequence of higher protein expression of Mitofusin-2 and OPA1 that could protect against mitophagy-mediated cell death.”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [116]

    Results §2.3 (page unavailable) says maternal diabetes impaired mitochondrial dynamics similarly in female and male rat cardiomyocytes, contrary to the claimed lack of effect in females. Results §2.5 reports higher OPA1 expression in diet-exposed males, not females; the Discussion also describes higher MFN2 as a possible contributor to cardiomyocyte death rather than protection from it. (LLM, conf=0.93)

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  • Mitochondrial dynamics in cardiomyocytes from female offspring were not affected by exposure to maternal diabetes.

    “Notably, mitochondrial dynamics in cardiomyocytes from the female offspring were not affected by exposure to maternal diabetes, likely as a consequence of higher protein expression of Mitofusin-2 and OPA1 that could protect against mitophagy-mediated cell death.”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [116]

    Results §2.3 states that diabetes and diet impaired mitochondrial dynamism in both female and male neonatal rat cardiomyocytes; it specifically concludes that diabetes exposure impaired dynamism similarly in both sexes. Although the Discussion reports higher fusion-protein expression in female hearts, that does not support the claim that maternal diabetes left their mitochondrial dynamics unaffected. (LLM, conf=0.93)

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  • In cardiomyocytes from male offspring from a high-fat diet and diabetes during pregnancy, mitochondrial fusion and fission events are reduced, but the balance is tipped in favour of more fission events over fusion events.

    “However, in cardiomyocytes from the male offspring from a high-fat diet and diabetes during pregnancy, mitochondrial fusion and fission events were reduced, but the balance was tipped in favour of more fission events over fusion events [116].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [116]

    Results §2.3 reports that diabetes and diet impaired mitochondrial dynamism in both sexes, supporting the reduction in events. But for high-fat-diet-exposed male cardiomyocytes, it reports an anti-fission ratio of 0.88, not a balance favoring fission. The Discussion likewise contrasts males’ anti-fission balance with females’ pro-fission balance. The paper does not establish the claimed pro-fission balance for males exposed to both diet and diabetes. (LLM, conf=0.90)

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  • There are impairments in the removal of damaged mitochondria in offspring cardiomyocytes after maternal high-fat feeding.

    “Maternal high-fat feeding also reduces mitochondrial fission and fusion events in offspring cardiomyocytes, suggesting that there are impairments in the removal of damaged mitochondria [116].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [116]

    The Discussion (page unavailable) reports reduced fission and fusion in offspring cardiomyocytes after maternal high-fat feeding. It suggests that the balance observed in males could adversely affect mitochondrial quality control, but does not establish impaired removal of damaged mitochondria; the Results (section 2.6, page unavailable) even suggest a possible increase in mitophagy in males. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Fetal cardiomyocytes from the high-fat diet and STZ-induced diabetes model demonstrated well-balanced fusion and fission events.

    “Fetal cardiomyocytes demonstrated well-balanced fusion and fission events.”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [116]

    Results §2.1 reports a balanced fission:fusion ratio of 0.99 in cardiomyocytes exposed to both maternal diabetes and a high-fat diet. But both types of event declined by 50%, and more mitochondria were adynamic and fragmented. Calling the events “well-balanced” without that qualification overstates the finding. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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References 83 · Cited by 57

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Authors
Larsen, T. D., Sabey, K. H., Knutson, A. J., Gandy, T. C. T., Louwagie, E. J., Lauterboeck, L., Mdaki, K. S., & Baack, M. L.
Affiliations
  • Sanford Research (US)
  • University of South Dakota (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Baack, Michelle L.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-06-25
Volume
20
Issue
12
Pages
3090
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms20123090
PMC
PMC6627740
OpenAlex
W2949571715
Cited by
57
References
83
Citations by year
2026: 6 · 2025: 10 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 10 · 2020: 6 · 2019: 2
FWCI
2.40
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (K08HD078504, P20GM103620)
  • National Science Foundation (DBI-1262744, IIA-1355423)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
diabetes in pregnancy, maternal high-fat diet, mitochondrial dynamics, mitochondrial fusion, mitochondrial fission, sex differences, neonatal cardiomyocytes, fetal heart development, diastolic dysfunction, systolic dysfunction, myocardial lipid accumulation, oxidative stress, mitophagy, post-translational modification
MeSH terms
Animals, Animals, Newborn, Female, Fluorescent Antibody Technique, Gene Expression Regulation, Heart, Male, Mitochondria, Heart, Pregnancy, Pregnancy in Diabetics, Protein Processing, Post-Translational, Sex Factors, Biomarkers, Mitochondrial Proteins, Myocytes, Cardiac, Organogenesis, Fetal Development, Rats, Diet, High-Fat, Mitochondrial Dynamics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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