Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance

Michael A Pearen, Joel M Goode, Rebecca L Fitzsimmons, Natalie A Eriksson, Gethin P Thomas, Gary J Cowin, S-C Mary Wang, Zewen K Tuong, George EO Muscat

    Research output: Contribution to journalArticle

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    Abstract

    The mRNA encoding Nor-1/NR4A3 is rapidly and strikingly induced by 2-adrenergic signaling in glycolytic and oxidative skeletal muscle. In skeletal muscle cells, Nor-1 expression is important for the regulation of oxidative metabolism. Transgenic skeletal muscle-specific expression of activated Nor-1 resulted in the acquisition of an endurance phenotype, an increase in type IIA/X oxidative muscle fibers, and increased numbers of mitochondria. In the current study, we used dual-energy x-ray absorptiometry and magnetic resonance imaging analysis to demonstrate decreased adiposity in transgenic (Tg) Nor-1 mice relative to that in wild-type littermates. Furthermore, the Tg-Nor-1 mice were resistant to diet-induced weight gain and maintained fasting glucose at normoglycemic levels. Expression profiling and RT-quantitative PCR analysis revealed significant increases in genes involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and glycogen synthesis, in concordance with the lean phenotype. Moreover, expression profiling identified several Z-disc and sarcomeric binding proteins that modulate fiber type phenotype and endurance, eg, α-actinin-3. In addition, we demonstrated that the Tg-Nor-1 mouse line has significantly higher glycogen content in skeletal muscle relative to that in wild-type littermates. Finally, we identified a decreased NAD+/NADH ratio with a concordant increase in peroxisome proliferator-activated receptor γcoactivator-1α1 protein/ mRNA expression. Increased NADH was associated with an induction of the genes involved in the malate-aspartate shuttle and a decrease in the glycerol 3-phosphate shuttle, which maximizes aerobic ATP production. In conclusion, skeletal muscle-specific Nor-1 expression regulates genes and pathways that regulate adiposity, muscle fiber type metabolic capacity, and endurance.
    Original languageEnglish
    Pages (from-to)1897-1917
    Number of pages21
    JournalMolecular Endocrinology
    Volume27
    Issue number11
    DOIs
    Publication statusPublished - 2013

    Fingerprint

    Adiposity
    Skeletal Muscle
    Muscles
    NAD
    Glycogen
    Phenotype
    Actinin
    Messenger RNA
    Peroxisome Proliferator-Activated Receptors
    Citric Acid Cycle
    Oxidative Phosphorylation
    Glycolysis
    Aspartic Acid
    Adrenergic Agents
    Muscle Cells
    Genes
    Weight Gain
    Fasting
    Carrier Proteins
    Mitochondria

    Cite this

    Pearen, M. A., Goode, J. M., Fitzsimmons, R. L., Eriksson, N. A., Thomas, G. P., Cowin, G. J., ... Muscat, G. EO. (2013). Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance. Molecular Endocrinology, 27(11), 1897-1917. https://doi.org/10.1210/me.2013-1205
    Pearen, Michael A ; Goode, Joel M ; Fitzsimmons, Rebecca L ; Eriksson, Natalie A ; Thomas, Gethin P ; Cowin, Gary J ; Wang, S-C Mary ; Tuong, Zewen K ; Muscat, George EO. / Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 11. pp. 1897-1917.
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    abstract = "The mRNA encoding Nor-1/NR4A3 is rapidly and strikingly induced by 2-adrenergic signaling in glycolytic and oxidative skeletal muscle. In skeletal muscle cells, Nor-1 expression is important for the regulation of oxidative metabolism. Transgenic skeletal muscle-specific expression of activated Nor-1 resulted in the acquisition of an endurance phenotype, an increase in type IIA/X oxidative muscle fibers, and increased numbers of mitochondria. In the current study, we used dual-energy x-ray absorptiometry and magnetic resonance imaging analysis to demonstrate decreased adiposity in transgenic (Tg) Nor-1 mice relative to that in wild-type littermates. Furthermore, the Tg-Nor-1 mice were resistant to diet-induced weight gain and maintained fasting glucose at normoglycemic levels. Expression profiling and RT-quantitative PCR analysis revealed significant increases in genes involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and glycogen synthesis, in concordance with the lean phenotype. Moreover, expression profiling identified several Z-disc and sarcomeric binding proteins that modulate fiber type phenotype and endurance, eg, α-actinin-3. In addition, we demonstrated that the Tg-Nor-1 mouse line has significantly higher glycogen content in skeletal muscle relative to that in wild-type littermates. Finally, we identified a decreased NAD+/NADH ratio with a concordant increase in peroxisome proliferator-activated receptor γcoactivator-1α1 protein/ mRNA expression. Increased NADH was associated with an induction of the genes involved in the malate-aspartate shuttle and a decrease in the glycerol 3-phosphate shuttle, which maximizes aerobic ATP production. In conclusion, skeletal muscle-specific Nor-1 expression regulates genes and pathways that regulate adiposity, muscle fiber type metabolic capacity, and endurance.",
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    Pearen, MA, Goode, JM, Fitzsimmons, RL, Eriksson, NA, Thomas, GP, Cowin, GJ, Wang, S-CM, Tuong, ZK & Muscat, GEO 2013, 'Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance', Molecular Endocrinology, vol. 27, no. 11, pp. 1897-1917. https://doi.org/10.1210/me.2013-1205

    Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance. / Pearen, Michael A; Goode, Joel M; Fitzsimmons, Rebecca L; Eriksson, Natalie A; Thomas, Gethin P; Cowin, Gary J; Wang, S-C Mary; Tuong, Zewen K; Muscat, George EO.

    In: Molecular Endocrinology, Vol. 27, No. 11, 2013, p. 1897-1917.

    Research output: Contribution to journalArticle

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    AU - Pearen, Michael A

    AU - Goode, Joel M

    AU - Fitzsimmons, Rebecca L

    AU - Eriksson, Natalie A

    AU - Thomas, Gethin P

    AU - Cowin, Gary J

    AU - Wang, S-C Mary

    AU - Tuong, Zewen K

    AU - Muscat, George EO

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    AB - The mRNA encoding Nor-1/NR4A3 is rapidly and strikingly induced by 2-adrenergic signaling in glycolytic and oxidative skeletal muscle. In skeletal muscle cells, Nor-1 expression is important for the regulation of oxidative metabolism. Transgenic skeletal muscle-specific expression of activated Nor-1 resulted in the acquisition of an endurance phenotype, an increase in type IIA/X oxidative muscle fibers, and increased numbers of mitochondria. In the current study, we used dual-energy x-ray absorptiometry and magnetic resonance imaging analysis to demonstrate decreased adiposity in transgenic (Tg) Nor-1 mice relative to that in wild-type littermates. Furthermore, the Tg-Nor-1 mice were resistant to diet-induced weight gain and maintained fasting glucose at normoglycemic levels. Expression profiling and RT-quantitative PCR analysis revealed significant increases in genes involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and glycogen synthesis, in concordance with the lean phenotype. Moreover, expression profiling identified several Z-disc and sarcomeric binding proteins that modulate fiber type phenotype and endurance, eg, α-actinin-3. In addition, we demonstrated that the Tg-Nor-1 mouse line has significantly higher glycogen content in skeletal muscle relative to that in wild-type littermates. Finally, we identified a decreased NAD+/NADH ratio with a concordant increase in peroxisome proliferator-activated receptor γcoactivator-1α1 protein/ mRNA expression. Increased NADH was associated with an induction of the genes involved in the malate-aspartate shuttle and a decrease in the glycerol 3-phosphate shuttle, which maximizes aerobic ATP production. In conclusion, skeletal muscle-specific Nor-1 expression regulates genes and pathways that regulate adiposity, muscle fiber type metabolic capacity, and endurance.

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