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Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC - PLoS ONE (2009)

Bottom Line: To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle.We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet.In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity.

View Article: PubMed Central - PubMed

Affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

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Tissue-specific inhibition of myostatin signaling.(A) Diagram of the construct used to make fat-DN transgenic mice with the aP2 promoter controlling expression of a truncated Acvr2b containing the extracellular ligand binding and transmembrane domains. (B) Northern blot analysis of expression of fat-DN transgene and Gapdh loading control from different tissues from non-transgenic (−) and transgenic (+) mice. Body composition of (C) fat-DN (n = 10–11) and (D) muscle-DN (n = 5) male mice compared to non-transgenic littermates. Lean and fat mass are shown as absolute values. Body weight gained by (E) fat-DN (n = 9–17) and (F) muscle-DN (n = 9–14) male mice and littermate controls after 10 weeks on diets. Blood glucose levels during GTT of (G) fat-DN (n = 7–8) and (H) muscle-DN (n = 9–14) male mice and littermate controls on standard chow and HFD. Percent of starting glucose during ITT of (I) fat-DN (n = 7–8) and (J) muscle-DN (n = 9–12) male mice and littermate controls on standard chow and HFD. *P<0.05, **P<0.01, ***P<0.001. G–J, P value symbols are for comparisons between genotypes on the same diet; below curves, mice on standard chow; above curves, mice on HFD.
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pone-0004937-g005: Tissue-specific inhibition of myostatin signaling.(A) Diagram of the construct used to make fat-DN transgenic mice with the aP2 promoter controlling expression of a truncated Acvr2b containing the extracellular ligand binding and transmembrane domains. (B) Northern blot analysis of expression of fat-DN transgene and Gapdh loading control from different tissues from non-transgenic (−) and transgenic (+) mice. Body composition of (C) fat-DN (n = 10–11) and (D) muscle-DN (n = 5) male mice compared to non-transgenic littermates. Lean and fat mass are shown as absolute values. Body weight gained by (E) fat-DN (n = 9–17) and (F) muscle-DN (n = 9–14) male mice and littermate controls after 10 weeks on diets. Blood glucose levels during GTT of (G) fat-DN (n = 7–8) and (H) muscle-DN (n = 9–14) male mice and littermate controls on standard chow and HFD. Percent of starting glucose during ITT of (I) fat-DN (n = 7–8) and (J) muscle-DN (n = 9–12) male mice and littermate controls on standard chow and HFD. *P<0.05, **P<0.01, ***P<0.001. G–J, P value symbols are for comparisons between genotypes on the same diet; below curves, mice on standard chow; above curves, mice on HFD.

Mentions: The metabolic changes we found in Mstn−/− mice could be due to the loss of myostatin signaling in adipose tissue as well as skeletal muscle. To determine whether inhibition of myostatin signaling in adipose tissue alters adipose tissue mass and glucose metabolism independent of increased skeletal muscle mass, we generated a transgenic mouse line expressing a dominant negative (DN) Acvr2b gene specifically in adipocytes. An aP2 (fatty acid binding protein 4) promoter fragment, previously used to control expression of transgenes in differentiated adipocytes [32], was inserted upstream of the Acvr2b coding sequence consisting of the extracellular ligand-binding and transmembrane domains without the intracellular kinase domain (Fig. 5A). This construct was used for pronuclear injections. Northern blot analysis of RNA from tissues obtained from mice expressing the adipose-specific dominant negative transgene (fat-DN) showed high transgene expression in white and brown adipose tissue (Fig. 5B). A low level of transgene expression was detectable in skeletal muscle either from leaky transgene expression in muscle cells or possibly from intermuscular adipocytes. Heart tissue similarly had low transgene expression. No signal was detectable in brain, liver, kidney, and testes (Fig. 5B and data not shown).


Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC - PLoS ONE (2009)

Tissue-specific inhibition of myostatin signaling.(A) Diagram of the construct used to make fat-DN transgenic mice with the aP2 promoter controlling expression of a truncated Acvr2b containing the extracellular ligand binding and transmembrane domains. (B) Northern blot analysis of expression of fat-DN transgene and Gapdh loading control from different tissues from non-transgenic (−) and transgenic (+) mice. Body composition of (C) fat-DN (n = 10–11) and (D) muscle-DN (n = 5) male mice compared to non-transgenic littermates. Lean and fat mass are shown as absolute values. Body weight gained by (E) fat-DN (n = 9–17) and (F) muscle-DN (n = 9–14) male mice and littermate controls after 10 weeks on diets. Blood glucose levels during GTT of (G) fat-DN (n = 7–8) and (H) muscle-DN (n = 9–14) male mice and littermate controls on standard chow and HFD. Percent of starting glucose during ITT of (I) fat-DN (n = 7–8) and (J) muscle-DN (n = 9–12) male mice and littermate controls on standard chow and HFD. *P<0.05, **P<0.01, ***P<0.001. G–J, P value symbols are for comparisons between genotypes on the same diet; below curves, mice on standard chow; above curves, mice on HFD.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654157&req=5

pone-0004937-g005: Tissue-specific inhibition of myostatin signaling.(A) Diagram of the construct used to make fat-DN transgenic mice with the aP2 promoter controlling expression of a truncated Acvr2b containing the extracellular ligand binding and transmembrane domains. (B) Northern blot analysis of expression of fat-DN transgene and Gapdh loading control from different tissues from non-transgenic (−) and transgenic (+) mice. Body composition of (C) fat-DN (n = 10–11) and (D) muscle-DN (n = 5) male mice compared to non-transgenic littermates. Lean and fat mass are shown as absolute values. Body weight gained by (E) fat-DN (n = 9–17) and (F) muscle-DN (n = 9–14) male mice and littermate controls after 10 weeks on diets. Blood glucose levels during GTT of (G) fat-DN (n = 7–8) and (H) muscle-DN (n = 9–14) male mice and littermate controls on standard chow and HFD. Percent of starting glucose during ITT of (I) fat-DN (n = 7–8) and (J) muscle-DN (n = 9–12) male mice and littermate controls on standard chow and HFD. *P<0.05, **P<0.01, ***P<0.001. G–J, P value symbols are for comparisons between genotypes on the same diet; below curves, mice on standard chow; above curves, mice on HFD.
Mentions: The metabolic changes we found in Mstn−/− mice could be due to the loss of myostatin signaling in adipose tissue as well as skeletal muscle. To determine whether inhibition of myostatin signaling in adipose tissue alters adipose tissue mass and glucose metabolism independent of increased skeletal muscle mass, we generated a transgenic mouse line expressing a dominant negative (DN) Acvr2b gene specifically in adipocytes. An aP2 (fatty acid binding protein 4) promoter fragment, previously used to control expression of transgenes in differentiated adipocytes [32], was inserted upstream of the Acvr2b coding sequence consisting of the extracellular ligand-binding and transmembrane domains without the intracellular kinase domain (Fig. 5A). This construct was used for pronuclear injections. Northern blot analysis of RNA from tissues obtained from mice expressing the adipose-specific dominant negative transgene (fat-DN) showed high transgene expression in white and brown adipose tissue (Fig. 5B). A low level of transgene expression was detectable in skeletal muscle either from leaky transgene expression in muscle cells or possibly from intermuscular adipocytes. Heart tissue similarly had low transgene expression. No signal was detectable in brain, liver, kidney, and testes (Fig. 5B and data not shown).

Bottom Line: To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle.We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet.In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity.

View Article: PubMed Central - PubMed

Affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

Show MeSH
Related in: MedlinePlus