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Cited by 56Muscle Physiology and DisordersMetabolism, Diabetes, and CancerAdipose Tissue and Metabolism

A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells

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Mughal, W, Nguyen, L, Pustylnik, S, da Silva Rosa, S C, Piotrowski, S, Chapman, D, Du, M, Alli, N S +12 more·2015·Cell Death & Disease
DOI 10.1038/cddis.2015.306PMC PMC5399178
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Abstract

Exposure to metabolic disease during fetal development alters cellular differentiation and perturbs metabolic homeostasis, but the underlying molecular regulators of this phenomenon in muscle cells are not completely understood. To address this, we undertook a computational approach to identify cooperating partners of the myocyte enhancer factor-2 (MEF2) family of transcription factors, known regulators of muscle differentiation and metabolic function. We demonstrate that MEF2 and the serum response factor (SRF) collaboratively regulate the expression of numerous muscle-specific genes, including microRNA-133a (miR-133a). Using tandem mass spectrometry techniques, we identify a conserved phosphorylation motif within the MEF2 and SRF M cm1 A gamous D eficiens S RF (MADS)-box that regulates miR-133a expression and mitochondrial function in response to a lipotoxic signal. Furthermore, reconstitution of MEF2 function by expression of a neutralizing mutation in this identified phosphorylation motif restores miR-133a expression and mitochondrial membrane potential during lipotoxicity. Mechanistically, we demonstrate that miR-133a regulates mitochondrial function through translational inhibition of a mitophagy and cell death modulating protein, called Nix. Finally, we show that rodents exposed to gestational diabetes during fetal development display muscle diacylglycerol accumulation, concurrent with insulin resistance, reduced miR-133a, and elevated Nix expression, as young adult rats. Given the diverse roles of miR-133a and Nix in regulating mitochondrial function, and proliferation in certain cancers, dysregulation of this genetic pathway may have broad implications involving insulin resistance, cardiovascular disease, and cancer biology.

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  • Mitochondrial dysfunction and impaired cell death pathways downstream contribute to insulin resistance in the muscle tissue of gestational diabetes mellitus-exposed offspring.

    “Consequently, mitochondrial dysfunction and impaired cell death pathways downstream contribute to insulin resistance in the muscle tissue of GDM-exposed offspring [105,106].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [106]

    The Results section ('Evaluation of miR-133a and Nix expression in vivo'; page unavailable) reports altered mitochondrial markers and increased Nix expression in the soleus muscle of gestational-diabetes-exposed rat offspring. The Discussion says this pathway may have implications for insulin resistance, but the paper does not establish that mitochondrial dysfunction or impaired cell-death pathways cause the offspring’s insulin resistance. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Metabolomic profiling of soleus muscle from rat offspring exposed to gestational diabetes mellitus revealed accumulation of diacylglycerols and alterations of the fatty acyl composition of phosphatidic acid and cardiolipin.

    “Metabolomic profiling of soleus muscle from the rat offspring exposed to GDM revealed the accumulation of diacylglycerols and alterations of the fatty acyl composition of phosphatidic acid and cardiolipin [106].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [106]

    The Results section (‘Evaluation of miR-133a and Nix expression in vivo’; page unavailable) reports metabolomic analysis and increased diacylglycerols in the soleus muscle of offspring exposed to gestational diabetes. Our copy does not report alterations in the fatty acyl composition of phosphatidic acid or cardiolipin; searches for those lipids did not find supporting passages. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Activation of Protein Kinase C-δ was associated with the metabolomic changes and inhibits insulin signalling in muscle tissue.

    “This was associated with activation of Protein Kinase C (PKC)-δ [106] which inhibits insulin signalling in muscle tissue [107].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [106]

  • Protein Kinase C-δ inhibited the expression of miR-133a, which elevated expression of its target, Nix, a mitophagy and cell-death-modulating protein.

    “Mechanistically, PKC-δ inhibited the expression of miR-133a, which elevated expression of its target, Nix, a mitophagy and cell-death-modulating protein [106].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [106]

  • Offspring exposed to gestational diabetes mellitus exhibited skeletal muscle lipotoxicity and insulin resistance.

    “Subsequent studies using this approach have demonstrated that offspring exposed to GDM exhibited skeletal muscle lipotoxicity and insulin resistance [105,106] (Figure 1).”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [106]

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Research works printed but not linked: 47

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Authors
Mughal, W., Nguyen, L., Pustylnik, S., da Silva Rosa, S. C., Piotrowski, S., Chapman, D., Du, M., Alli, N. S., Grigull, J., Halayko, A. J., Aliani, M., Topham, M. K., Epand, R. M., Hatch, G. M., Pereira, T. J., Kereliuk, S., McDermott, J. C., Rampitsch, C., Dolinsky, V. W., & Gordon, J. W.
Affiliations
  • Children's Hospital Research Institute of Manitoba (CA)
  • York University (CA)
  • University of Manitoba (CA)
  • Huntsman Cancer Institute (US)
  • McMaster University (CA)
  • Agriculture and Agri-Food Canada (CA)
Corresponding author
Gordon, J W
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2015-10-29
Volume
6
Issue
10
Pages
e1944-e1944
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/cddis.2015.306
PMC
PMC5399178
OpenAlex
W2258479317
Cited by
56
References
52
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 6 · 2016: 4
FWCI
2.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Heart and Stroke Foundation of Canada
  • Manitoba Health Research Council
  • Manitoba Medical Service Foundation
  • Children's Hospital Foundation
  • Canada Research Chairs
  • Canadian Institutes of Health Research
  • Natural Sciences and Engineering Research Council of Canada
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
MEF2, serum response factor, miR-133a, Nix, mitochondrial function, lipotoxicity, myogenesis, gestational diabetes mellitus, insulin resistance, diacylglycerol, mitophagy, mitochondrial membrane potential, skeletal muscle, myocardium, smooth muscle, fetal development
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Chlorocebus aethiops, Female, Gene Expression Regulation, Humans, Mitochondria, Phosphorylation, Pregnancy, Prenatal Exposure Delayed Effects, Mutagenesis, Site-Directed, Diabetes, Gestational, Muscle Fibers, Skeletal, COS Cells, Amino Acid Motifs, Serum Response Factor, Myocytes, Cardiac, Myocytes, Smooth Muscle, MicroRNAs, Rats, Membrane Potential, Mitochondrial, Tandem Mass Spectrometry, MEF2 Transcription Factors

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