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Redundancy of myostatin and growth/differentiation factor 11 function.

McPherron AC, Huynh TV, Lee SJ - BMC Dev. Biol. (2009)

Bottom Line: Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes.In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules.We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn+/+ or Mstn-/- mice does not affect muscle size, fiber number, or fiber type.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. mcpherrona@niddk.nih.gov

ABSTRACT

Background: Myostatin (Mstn) and growth/differentiation factor 11 (Gdf11) are highly related transforming growth factor beta (TGFbeta) family members that play important roles in regulating embryonic development and adult tissue homeostasis. Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of Gdf11 in mice causes dramatic anterior homeotic transformations of the axial skeleton, kidney agenesis, and an increase in progenitor cell number in several tissues. In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules.

Results: We show that Mstn-/- Gdf11-/- mice have more extensive homeotic transformations of the axial skeleton than Gdf11-/- mice in addition to skeletal defects not seen in single mutants such as extra forelimbs. We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn+/+ or Mstn-/- mice does not affect muscle size, fiber number, or fiber type.

Conclusion: These results provide evidence that myostatin and Gdf11 have redundant functions in regulating skeletal patterning in mice but most likely not in regulating muscle size.

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Muscle weight, fiber number, and fiber type in skeletal muscle-specific Gdf11 mutant mice in a Mstn wild-type or  background. (A) Weight of pectoralis, triceps, quadriceps, gastrocnemius/plantaris, and tibialis anterior muscles (n = 7–12). (B) Number of total, IIA, IID/X, and IIB fibers in the EDL muscle (n = 3–4). EDL muscles had on average less than 4 type I fibers in all genotypes so type I data are not shown. (C) Number of total, type I, IIA, IID/X, and IIB fibers in the soleus muscle (n = 3–5). Skeletal muscle-specific Gdf11 deletion had no effect on muscle mass, fiber number, or fiber type unlike Mstn deletion (*P < 0.05, †P < 0.01, ‡P < 0.001). Data are mean ± s.e.
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Figure 3: Muscle weight, fiber number, and fiber type in skeletal muscle-specific Gdf11 mutant mice in a Mstn wild-type or background. (A) Weight of pectoralis, triceps, quadriceps, gastrocnemius/plantaris, and tibialis anterior muscles (n = 7–12). (B) Number of total, IIA, IID/X, and IIB fibers in the EDL muscle (n = 3–4). EDL muscles had on average less than 4 type I fibers in all genotypes so type I data are not shown. (C) Number of total, type I, IIA, IID/X, and IIB fibers in the soleus muscle (n = 3–5). Skeletal muscle-specific Gdf11 deletion had no effect on muscle mass, fiber number, or fiber type unlike Mstn deletion (*P < 0.05, †P < 0.01, ‡P < 0.001). Data are mean ± s.e.

Mentions: Body weight and muscle mass were measured in all 8 possible genotypes produced from crosses of Gdf11flox/+ MLC-Cre and Gdf11+/- mice. There were no differences in body weight or muscle mass between Gdf11+/+, Gdf11+/+ MLC-Cre, Gdf11+/-, Gdf11+/- MLC-Cre, Gdf11flox/+, or Gdf11flox/+ MLC-Cre mice demonstrating that there was no heterozygous or transgene phenotype (data not shown). We next performed an examination of the muscle phenotype of Gdf11flox/- and Gdf11flox/- MLC-Cre mice. There was no statistically significant difference in body weight or muscle mass between Gdf11flox/- and Gdf11flox/- MLC-Cre mice (data not shown and Figure 3A).


Redundancy of myostatin and growth/differentiation factor 11 function.

McPherron AC, Huynh TV, Lee SJ - BMC Dev. Biol. (2009)

Muscle weight, fiber number, and fiber type in skeletal muscle-specific Gdf11 mutant mice in a Mstn wild-type or  background. (A) Weight of pectoralis, triceps, quadriceps, gastrocnemius/plantaris, and tibialis anterior muscles (n = 7–12). (B) Number of total, IIA, IID/X, and IIB fibers in the EDL muscle (n = 3–4). EDL muscles had on average less than 4 type I fibers in all genotypes so type I data are not shown. (C) Number of total, type I, IIA, IID/X, and IIB fibers in the soleus muscle (n = 3–5). Skeletal muscle-specific Gdf11 deletion had no effect on muscle mass, fiber number, or fiber type unlike Mstn deletion (*P < 0.05, †P < 0.01, ‡P < 0.001). Data are mean ± s.e.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666675&req=5

Figure 3: Muscle weight, fiber number, and fiber type in skeletal muscle-specific Gdf11 mutant mice in a Mstn wild-type or background. (A) Weight of pectoralis, triceps, quadriceps, gastrocnemius/plantaris, and tibialis anterior muscles (n = 7–12). (B) Number of total, IIA, IID/X, and IIB fibers in the EDL muscle (n = 3–4). EDL muscles had on average less than 4 type I fibers in all genotypes so type I data are not shown. (C) Number of total, type I, IIA, IID/X, and IIB fibers in the soleus muscle (n = 3–5). Skeletal muscle-specific Gdf11 deletion had no effect on muscle mass, fiber number, or fiber type unlike Mstn deletion (*P < 0.05, †P < 0.01, ‡P < 0.001). Data are mean ± s.e.
Mentions: Body weight and muscle mass were measured in all 8 possible genotypes produced from crosses of Gdf11flox/+ MLC-Cre and Gdf11+/- mice. There were no differences in body weight or muscle mass between Gdf11+/+, Gdf11+/+ MLC-Cre, Gdf11+/-, Gdf11+/- MLC-Cre, Gdf11flox/+, or Gdf11flox/+ MLC-Cre mice demonstrating that there was no heterozygous or transgene phenotype (data not shown). We next performed an examination of the muscle phenotype of Gdf11flox/- and Gdf11flox/- MLC-Cre mice. There was no statistically significant difference in body weight or muscle mass between Gdf11flox/- and Gdf11flox/- MLC-Cre mice (data not shown and Figure 3A).

Bottom Line: Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes.In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules.We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn+/+ or Mstn-/- mice does not affect muscle size, fiber number, or fiber type.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. mcpherrona@niddk.nih.gov

ABSTRACT

Background: Myostatin (Mstn) and growth/differentiation factor 11 (Gdf11) are highly related transforming growth factor beta (TGFbeta) family members that play important roles in regulating embryonic development and adult tissue homeostasis. Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of Gdf11 in mice causes dramatic anterior homeotic transformations of the axial skeleton, kidney agenesis, and an increase in progenitor cell number in several tissues. In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules.

Results: We show that Mstn-/- Gdf11-/- mice have more extensive homeotic transformations of the axial skeleton than Gdf11-/- mice in addition to skeletal defects not seen in single mutants such as extra forelimbs. We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn+/+ or Mstn-/- mice does not affect muscle size, fiber number, or fiber type.

Conclusion: These results provide evidence that myostatin and Gdf11 have redundant functions in regulating skeletal patterning in mice but most likely not in regulating muscle size.

Show MeSH
Related in: MedlinePlus