Gene expression of key regulators of mitochondrial biogenesis is sex dependent in mice with growth hormone receptor deletion in liver

Mitochondrial biogenesis is an essential process for cell viability. Mice with disruption of the growth hormone receptor (GHR) gene (Ghr gene) in the liver (LiGHRKO), in contrast to long-lived mice with global deletion of the Ghr gene (GHRKO), are characterized by lack of improved insulin sensitivity and severe hepatic steatosis. Tissue-specific disruption of the GHR in liver results in a mouse model with dramatically altered GH/IGF1 axis. We have previously shown increased levels of key regulators of mitochondrial biogenesis in insulin-sensitive GHRKO mice. The aim of the present study is to assess, using real-time PCR, the gene expression of key regulators of mitochondrial biogenesis (Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2) and a marker of mitochondrial activity (CoxIV) in brains, kidneys and livers of male and female LiGHRKO and wild-type (WT) mice. There were significant differences between males and females. In the brain, expression of Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2 was lower in pooled females compared to pooled males. In the kidneys, expression of Ampk and Sirt1 was also lower in female mice. In the liver, no differences between males and females were observed. Sexual dimorphism may play an important role in regulating the biogenesis of mitochondria.

[1]  Junling Wang,et al.  GABP Transcription Factor (Nuclear Respiratory Factor 2) Is Required for Mitochondrial Biogenesis , 2014, Molecular and Cellular Biology.

[2]  A. Proenza,et al.  Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle. , 2014, The Journal of endocrinology.

[3]  Magdalena Gianotti,et al.  Opposite effects of 17-β estradiol and testosterone on mitochondrial biogenesis and adiponectin synthesis in white adipocytes. , 2014, Journal of molecular endocrinology.

[4]  M. Beekman,et al.  Low mitochondrial DNA content associates with familial longevity: the Leiden Longevity Study , 2014, AGE.

[5]  Elizabeth A. Jensen,et al.  Liver-specific GH receptor gene-disrupted (LiGHRKO) mice have decreased endocrine IGF-I, increased local IGF-I, and altered body size, body composition, and adipokine profiles. , 2014, Endocrinology.

[6]  M. Johnston,et al.  Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation , 2014, BMC Neuroscience.

[7]  A. Malik,et al.  Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? , 2013, Mitochondrion.

[8]  A. Lewiński,et al.  Decreased levels of proapoptotic factors and increased key regulators of mitochondrial biogenesis constitute new potential beneficial features of long-lived growth hormone receptor gene-disrupted mice. , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[9]  J. Kopchick,et al.  The GH/IGF-1 axis in ageing and longevity , 2013, Nature Reviews Endocrinology.

[10]  B. Miller,et al.  Assessment of mitochondrial biogenesis and mTORC1 signaling during chronic rapamycin feeding in male and female mice. , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[11]  A. Hevener,et al.  The role of estrogens in control of energy balance and glucose homeostasis. , 2013, Endocrine reviews.

[12]  M. Beekman,et al.  Gene expression analysis of mTOR pathway: association with human longevity , 2013, Aging cell.

[13]  A. Bartke,et al.  The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice. , 2013, Molecular endocrinology.

[14]  Rick B. Vega,et al.  Transcriptional integration of mitochondrial biogenesis , 2012, Trends in Endocrinology & Metabolism.

[15]  A. Lewiński,et al.  Decreased thyroid follicle size in dwarf mice may suggest the role of growth hormone signaling in thyroid growth regulation , 2012, Thyroid Research.

[16]  A. Rebelo,et al.  The role of PGC‐1 coactivators in aging skeletal muscle and heart , 2012, IUBMB life.

[17]  D. Leroith,et al.  Targeted Loss of GHR Signaling in Mouse Skeletal Muscle Protects Against High-Fat Diet–Induced Metabolic Deterioration , 2011, Diabetes.

[18]  D. Joanisse,et al.  Mitochondrial Dysregulation in the Pathogenesis of Diabetes: Potential for Mitochondrial Biogenesis-Mediated Interventions , 2011, Experimental diabetes research.

[19]  A. Lewiński,et al.  Expression of key regulators of mitochondrial biogenesis in growth hormone receptor knockout (GHRKO) mice is enhanced but is not further improved by other potential life-extending interventions. , 2011, The journals of gerontology. Series A, Biological sciences and medical sciences.

[20]  A. Bartke,et al.  Key regulators of mitochondrial biogenesis are increased in kidneys of growth hormone receptor knockout (GHRKO) mice , 2011, Cell biochemistry and function.

[21]  J. Kopchick,et al.  Endocrine parameters and phenotypes of the growth hormone receptor gene disrupted (GHR-/-) mouse. , 2011, Endocrine reviews.

[22]  Chengyu Liu,et al.  Growth hormone receptor regulates β cell hyperplasia and glucose-stimulated insulin secretion in obese mice. , 2011, The Journal of clinical investigation.

[23]  A. Bartke,et al.  Renal pro-apoptotic proteins are reduced by growth hormone resistance but not by visceral fat removal , 2011, Biological chemistry.

[24]  A. Bartke,et al.  Deletion of growth hormone receptor gene but not visceral fat removal decreases expression of apoptosis-related genes in the kidney—potential mechanism of lifespan extension , 2011, AGE.

[25]  A. Lewiński,et al.  Decreased expression level of apoptosis-related genes and/or proteins in skeletal muscles, but not in hearts, of growth hormone receptor knockout mice , 2011, Experimental biology and medicine.

[26]  I. Robinson,et al.  Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood , 2010, Proceedings of the National Academy of Sciences.

[27]  T. van Groen,et al.  Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice. , 2010, The Journal of clinical investigation.

[28]  S. Melmed.  Acromegaly pathogenesis and treatment. , 2009, The Journal of clinical investigation.

[29]  T. Clemens,et al.  Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism*♦ , 2009, The Journal of Biological Chemistry.

[30]  Anastasia Kralli,et al.  Transcriptional control of mitochondrial biogenesis and function. , 2009, Annual review of physiology.

[31]  D. Befroy,et al.  Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis , 2007, Cell metabolism.

[32]  J. Bermúdez,et al.  Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis. , 2005, American journal of physiology. Cell physiology.

[33]  A. Bartke,et al.  Effects of caloric restriction on insulin pathway gene expression in the skeletal muscle and liver of normal and long-lived GHR-KO mice , 2005, Experimental Gerontology.

[34]  J. McCaffery,et al.  Structural Basis of Mitochondrial Tethering by Mitofusin Complexes , 2004, Science.

[35]  J. Zierath,et al.  Mitofusin-2 Determines Mitochondrial Network Architecture and Mitochondrial Metabolism , 2003, The Journal of Biological Chemistry.

[36]  T. Wagner,et al.  A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. MacLeod,et al.  Sex differences in the ultradian pattern of plasma growth hormone concentrations in mice. , 1991, The Journal of endocrinology.

[38]  A. Lewiński,et al.  Expression of apoptosis-related genes in liver-specific growth hormone receptor gene-disrupted mice is sex dependent. , 2015, The journals of gerontology. Series A, Biological sciences and medical sciences.

[39]  W. Malorni,et al.  Sex differences at cellular level: "cells have a sex". , 2012, Handbook of experimental pharmacology.

[40]  M. Bauzá-Thorbrügge,et al.  Sex-dependent differences in rat brown adipose tissue mitochondrial biogenesis and insulin signaling parameters in response to an obesogenic diet , 2012, Molecular and Cellular Biochemistry.

[41]  Min-Yu Chung,et al.  Two-year body composition analyses of long-lived GHR null mice. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.