Effect of Myostatin Depletion on Weight Gain, Hyperglycemia, and Hepatic Steatosis during Five Months of High-Fat Feeding in Mice

University of California, Los Angeles, and Cedars-Sinai Medical Center, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2011; 6(2):e17090. DOI: 10.1371/journal.pone.0017090
Source: PubMed


The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ∼30%. Hypermuscular mice had ∼50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet.

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Available from: Tianshun Xu, Jul 25, 2014
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    • "In addition, life-long genetic myostatin blockade, global or muscle-specific, prevents diet-induced increment in fat mass [1]–[3], [5], a phenotype that was also not reproducible in mice with adult age myostatin inhibition ([19], this work). However, despite a modest impact on body composition, adult age myostatin inhibition does prove effective in protection against diet-induced fatty liver ([19], this work) and atherosclerosis (this work), thus prompting us to consider organ-specific effect of myostatin (and its inhibitors) on metabolic regulations without being overwhelmed by the hyper-muscular phenotype found in mice with life-long genetic myostatin blockade. "
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    ABSTRACT: Genetic disruption of myostatin or its related signaling is known to cause strong protection against diet-induced metabolic disorders. The translational value of these prior findings, however, is dependent on whether such metabolically favorable phenotype can be reproduced when myostatin blockade begins at an adult age. Here, we reported that AAV-mediated delivery of a myostatin pro-peptide D76A mutant in adult mice attenuates the development of hepatic steatosis and arteriosclerosis, two common diet-induced metabolic diseases. A single dose of AAV-D76A in adult Ldlr null mice resulted in sustained expression of myostatin pro-peptide in the liver. Compared to vehicle-treated mice, D76A-treated mice gained similar amount of lean and fat mass when fed a high fat diet. However, D76A-treated mice displayed significantly reduced aortic lesions and liver fat, in association with a reduction in hepatic expression of lipogenic genes and improvement in liver insulin sensitivity. This suggests that muscle and fat may not be the primary targets of treatment under our experimental condition. In support to this argument, we show that myostatin directly up-regulated lipogenic genes and increased fat accumulation in cultured liver cells. We also show that both myostatin and its receptor were abundantly expressed in mouse aorta. Cultured aortic endothelial cells responded to myostatin with a reduction in eNOS phosphorylation and an increase in ICAM-1 and VCAM-1 expression. AAV-mediated expression of myostatin pro-peptide D76A mutant in adult Ldlr null mice sustained metabolic protection without remarkable impacts on body lean and fat mass. Further investigations are needed to determine whether direct impact of myostatin on liver and aortic endothelium may contribute to the related metabolic phenotypes.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "Myostatin knockout mice have a dramatic increase in muscle mass, a reduction in fat mass and a resistance to obesity caused by diet and genetic mutation (McPherron and Lee, 2002; Guo et al., 2009). Because muscle is a significant glucose consumer, it is not surprising that constitutive myostatin depletion by conditional genetic mutation (Wilkes et al., 2009; Burgess et al., 2011) and application of a myostatin receptor blocker (Akpan et al., 2009) can reduce weight gain and improve hyperglycemia, IR and hepatic steatosis caused by a high-fat diet in mice. Follistatin is known to be the most potent antagonist of myostatin (Lee and McPherron, 2001; Haidet et al., 2008) and has been reported as a candidate gene for women with PCOS (Urbanek et al., 1999). "
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    ABSTRACT: STUDY QUESTION What is the role of myostatin and its relationship with obesity, androgens and follistatin levels in women with polycystic ovary syndrome (PCOS)?
    Full-text · Article · Jun 2012 · Human Reproduction
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    • "Although it has been shown that adult tamoxifen administration had no effect on subsequent testing of several behavioral parameters [69], it has not been clarified whether this is also true for tamoxifen application during development. Only recently, several studies reported on successful recombination after administration of tamoxifen citrate via mouse chow [70], [71], [72], [73]. "
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    ABSTRACT: The serotonergic (5-HT) neuronal system has important and diverse physiological functions throughout development and adulthood. Its dysregulation during development or later in adulthood has been implicated in many neuropsychiatric disorders. Transgenic animal models designed to study the contribution of serotonergic susceptibility genes to a pathological phenotype should ideally allow to study candidate gene overexpression or gene knockout selectively in serotonergic neurons at any desired time during life. For this purpose, conditional expression systems such as the tet-system are preferable. Here, we generated a transactivator (tTA) mouse line (TPH2-tTA) that allows temporal and spatial control of tetracycline (Ptet) controlled transgene expression as well as gene deletion in 5-HT neurons. The tTA cDNA was inserted into a 196 kb PAC containing a genomic mouse Tph2 fragment (177 kb) by homologous recombination in E. coli. For functional analysis of Ptet-controlled transgene expression, TPH2-tTA mice were crossed to a Ptet-regulated lacZ reporter line (Ptet-nLacZ). In adult double-transgenic TPH2-tTA/Ptet-nLacZ mice, TPH2-tTA founder line L62-20 showed strong serotonergic β-galactosidase expression which could be completely suppressed with doxycycline (Dox). Furthermore, Ptet-regulated gene expression could be reversibly activated or inactivated when Dox was either withdrawn or added to the system. For functional analysis of Ptet-controlled, Cre-mediated gene deletion, TPH2-tTA mice (L62-20) were crossed to double transgenic Ptet-Cre/R26R reporter mice to generate TPH2-tTA/Ptet-Cre/R26R mice. Without Dox, 5-HT specific recombination started at E12.5. With permanent Dox administration, Ptet-controlled Cre-mediated recombination was absent. Dox withdrawal either postnatally or during adulthood induced efficient recombination in serotonergic neurons of all raphe nuclei, respectively. In the enteric nervous system, recombination could not be detected. We generated a transgenic mouse tTA line (TPH2-tTA) which allows both inducible and reversible transgene expression and inducible Cre-mediated gene deletion selectively in 5-HT neurons throughout life. This will allow precise delineation of serotonergic gene functions during development and adulthood.
    Full-text · Article · May 2012 · PLoS ONE
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