Gs deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency
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.
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- "There is increasing evidence that developmental plasticity alters the central regulation of homeostatic axes such as those involved in control of blood volume, stress susceptibility and energy balance   . Many imprinted genes show high expression in key components of the hypothalamo-pituitary axis (our observations;  ) and although genetic mouse models of altered dosage at the Dlk1- Dio3, Peg3 and Gnas loci show altered ''set points'' of metabolic axes there is, to our knowledge, currently no data linking changes in the early life environment with changes in the central nervous system expression of imprinted genes    . "
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 · 3.17 Impact Factor
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- "Skeletal-muscle G s α specific have impaired glucose tolerance in the absence of insulin deficiency and resistance, most likely as the result of reduced skeletal muscle mass. In addition, there appears to be a switch of the muscle fiber type towards aerobic, slow twitch (red) fibers even though the muscles have metabolic characteristics more typical of anaerobic, fast-twitch (white) fibers (Chen et al., 2009a). Adipose tissue-specific G s α knockout mice have markedly impaired adipogenesis (Chen et al., 2010). "
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 · 2.53 Impact Factor
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- "This loss in force is due to altered glucose metabolism and/or lack of circulating insulin since DPH muscles from 12-week diabetic animals supplemented with insulin for 2 weeks presented a complete reversal of this detrimental effect. A recent study in muscle-specific G protein α-subunit (Gsα) knockout mice  showed that this disruption of insulin signaling in skeletal muscles resulted in an adaptive fiber-type switch toward increased slow fiber contents in the absence of hyperglycemia. The results in our present study are consistent with this observation and further demonstrate a beneficial effect of the increase in slow fibers on compensating fatigue tolerance in diabetes. "
ABSTRACT: Diabetes is characterized by ventilatory depression due to decreased diaphragm (DPH) function. This study investigated the changes in contractile properties of rat DPH muscles over a time interval encompassing from 4 days to 14 weeks after the onset of streptozotocin-induced diabetes, with and without insulin treatment for 2 weeks. Maximum tetanic force in intact DPH muscle strips and recovery from fatiguing stimulation were measured. An early (4-day) depression in contractile function in diabetic DPH was followed by gradual improvement in muscle function and fatigue recovery (8 weeks). DPH contractile function deteriorated again at 14 weeks, a process that was completely reversed by insulin treatment. Maximal contractile force and calcium sensitivity assessed in Triton-skinned DPH fibers showed a similar bimodal pattern and the same beneficial effect of insulin treatment. While an extensive analysis of the isoforms of the contractile and regulatory proteins was not conducted, Western blot analysis of tropomyosin suggests that the changes in diabetic DPH response depended, at least in part, on a switch in fiber type.BioMed Research International 05/2010; 2010(1110-7243):931903. DOI:10.1155/2010/931903 · 2.71 Impact Factor