Gsα deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency

Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752, USA.
AJP Cell Physiology (Impact Factor: 3.67). 02/2009; 296(4):C930-40. DOI: 10.1152/ajpcell.00443.2008
Source: PubMed

ABSTRACT The ubiquitously expressed G protein alpha-subunit G(s)alpha is required for receptor-stimulated intracellular cAMP responses and is an important regulator of energy and glucose metabolism. We have generated skeletal muscle-specific G(s)alpha-knockout (KO) mice (MGsKO) by mating G(s)alpha-floxed mice with muscle creatine kinase-cre transgenic mice. MGsKO mice had normal body weight and composition, and their serum glucose, insulin, free fatty acid, and triglyceride levels were similar to that of controls. However, MGsKO mice were glucose intolerant despite the fact that insulin sensitivity and glucose-stimulated insulin secretion were normal, suggesting an insulin-independent mechanism. Isolated muscles from MGsKO mice had increased basal glucose uptake and normal responses to a stimulator of AMP-activated protein kinase (AMPK), which indicates that AMPK and its downstream pathways are intact. Compared with control mice, MGsKO mice had reduced muscle mass with decreased cross-sectional area and force production. In addition, adult MGsKO mice showed an increased proportion of type I (slow-twitch, oxidative) fibers based on kinetic properties and myosin heavy chain isoforms, despite the fact that these muscles had reduced expression of peroxisome proliferator-activated receptor coactivator protein-1alpha (PGC-1alpha) and reduced mitochondrial content and oxidative capacity. Therefore G(s)alpha deficiency led to fast-to-slow fiber-type switching, which appeared to be dissociated from the expected change in oxidative capacity. MGsKO mice are a valuable model for future studies of the role of G(s)alpha signaling pathways in skeletal muscle adaptation and their effects on whole body metabolism.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Developmental plasticity can be defined as the ability of one genotype to produce a range of phenotypes in response to environmental conditions. Such plasticity can be manifest at the level of individual cells, an organ, or a whole organism. Imprinted genes are a group of approximately 100 genes with functionally monoallelic, parental-origin specific expression. As imprinted genes are critical for prenatal growth and metabolic axis development and function, modulation of imprinted gene dosage has been proposed to play a key role in the plastic development of the unborn foetus in response to environmental conditions. Evidence is accumulating that imprinted dosage may also be involved in controlling the plastic potential of individual cells or stem cell populations. Imprinted gene dosage can be modulated through canonical, transcription factor mediated mechanisms, or through the relaxation of imprinting itself, reactivating the normally silent allele.
    FEBS letters 06/2011; 585(13):2059-66. DOI:10.1016/j.febslet.2011.05.063 · 3.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: G(s)α is a ubiquitously expressed G protein α-subunit that couples receptors to the generation of intracellular cyclic AMP. The G(s)α gene GNAS is a complex gene that undergoes genomic imprinting, an epigenetic phenomenon that leads to differential expression from the two parental alleles. G(s)α is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in a small number of tissues. Albright hereditary osteodystrophy is a monogenic obesity disorder caused by heterozygous G(s)α mutations but only when the mutations are maternally inherited. Studies in mice indicate a similar parent-of-origin effect on energy and glucose metabolism, with maternal but not paternal mutations leading to obesity, reduced sympathetic nerve activity and energy expenditure, glucose intolerance and insulin resistance, with no primary effect on food intake. These effects result from G(s)α imprinting leading to severe G(s)α deficiency in one or more regions of the central nervous system, and are associated with a specific defect in melanocortins to stimulate sympathetic nerve activity and energy expenditure.
    European journal of pharmacology 06/2011; 660(1):119-24. DOI:10.1016/j.ejphar.2010.10.105 · 2.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents basic characteristics of the room temperature plasma oxidation (RTPO) process for preparation of less than 2 nn thick layers of SiO<sub>2</sub> and high k layers of TiO<sub>2</sub>. The oxidation rate follows a power law with a proportionality constant depending on pressure, plasma power, temperature and reagent gas. The exponent depends only on the reactive gas. Surface roughness similar to thermal oxide films, surface state density below 3×10<sup>11</sup> cm<sup>-2</sup> and current density in the expected range for each corresponding thickness, were obtained by RTPO in a parallel plate reactor, at 180 mW/cm<sup>2</sup> and pressure range between 0.07 and 0.5 torn using O<sub>2</sub> as reactive gas. MOS capacitors with TiO<sub>2</sub> and stacked layers of TiO<sub>2</sub> over SiO<sub>2</sub> with equivalent thickness down to 2 nm were obtained and characterized.
    Solid-State and Integrated Circuits Technology, 2004. Proceedings. 7th International Conference on; 11/2004