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Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice.

Sengle G, Carlberg V, Tufa SF, Charbonneau NL, Smaldone S, Carlson EJ, Ramirez F, Keene DR, Sakai LY - PLoS Genet. (2015)

Bottom Line: These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy.In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development.New evidence presented here suggests that fibrillin-2 can sequester BMP complexes in a latent state.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America; Shriners Hospital for Children, Portland, Oregon, United States of America.

ABSTRACT
Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin-2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 mice (on a 129/Sv background) are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that fibrillin-2 can sequester BMP complexes in a latent state.

No MeSH data available.


Related in: MedlinePlus

Effects of genetic ablation of one allele of Bmp7 on Fbn2  forearm muscle and fat.(A) Series of sections (numbered at the top) generated by micro-CT of forearms from Fbn2-/-;Bmp7+/- mice (compare with Fig 2D). (B) Quantitation of percentages of muscle and fat across the genotypes. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 1 mm.
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pgen.1005340.g007: Effects of genetic ablation of one allele of Bmp7 on Fbn2 forearm muscle and fat.(A) Series of sections (numbered at the top) generated by micro-CT of forearms from Fbn2-/-;Bmp7+/- mice (compare with Fig 2D). (B) Quantitation of percentages of muscle and fat across the genotypes. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 1 mm.

Mentions: Since Bmp7 was highly expressed in P0 mouse forelimb muscle and since addition of BMP-7 to forelimb organ cultures resulted in an increase in the numbers of myofibers with centrally localized nuclei, we hypothesized that lowering the expression level of Bmp7 should have beneficial effects on the Fbn2 myopathy. To test this hypothesis, Fbn2+/- mice were crossed with Bmp7+/- mice [27] to generate Fbn2+/-; Bmp7+/- double heterozygous mice. Fbn2+/-; Bmp7+/- mice were then crossed with each other to generate Fbn2-/-; Bmp7+/- mice. Analysis and quantitation of forelimb muscle and fat was performed by μCT, after fixation and incubation of limbs with OsO4. A series of digital sections from Fbn2+/-; Bmp7+/- forelimb is shown in Fig 7A. The percentages of fat on comparable μCT sections of Fbn2 and wildtype littermates were quantitated relative to the areas of bone and muscle. Fat in Fbn2 forearms was significantly increased by two-fold over wildtype (p = 0.003; Fig 7B). Analysis of Fbn2-/-; Bmp7+/- forelimbs showed that the amount of fat and muscle on serial digital cross sections returned to normal wildtype levels (Fig 7B). This genetic approach provided further evidence that activated BMP signaling caused the Fbn2 myopathy, including both the reduction in muscle mass and the increase in fat that infiltrates the forelimb muscle.


Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice.

Sengle G, Carlberg V, Tufa SF, Charbonneau NL, Smaldone S, Carlson EJ, Ramirez F, Keene DR, Sakai LY - PLoS Genet. (2015)

Effects of genetic ablation of one allele of Bmp7 on Fbn2  forearm muscle and fat.(A) Series of sections (numbered at the top) generated by micro-CT of forearms from Fbn2-/-;Bmp7+/- mice (compare with Fig 2D). (B) Quantitation of percentages of muscle and fat across the genotypes. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 1 mm.
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Related In: Results  -  Collection

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pgen.1005340.g007: Effects of genetic ablation of one allele of Bmp7 on Fbn2 forearm muscle and fat.(A) Series of sections (numbered at the top) generated by micro-CT of forearms from Fbn2-/-;Bmp7+/- mice (compare with Fig 2D). (B) Quantitation of percentages of muscle and fat across the genotypes. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 1 mm.
Mentions: Since Bmp7 was highly expressed in P0 mouse forelimb muscle and since addition of BMP-7 to forelimb organ cultures resulted in an increase in the numbers of myofibers with centrally localized nuclei, we hypothesized that lowering the expression level of Bmp7 should have beneficial effects on the Fbn2 myopathy. To test this hypothesis, Fbn2+/- mice were crossed with Bmp7+/- mice [27] to generate Fbn2+/-; Bmp7+/- double heterozygous mice. Fbn2+/-; Bmp7+/- mice were then crossed with each other to generate Fbn2-/-; Bmp7+/- mice. Analysis and quantitation of forelimb muscle and fat was performed by μCT, after fixation and incubation of limbs with OsO4. A series of digital sections from Fbn2+/-; Bmp7+/- forelimb is shown in Fig 7A. The percentages of fat on comparable μCT sections of Fbn2 and wildtype littermates were quantitated relative to the areas of bone and muscle. Fat in Fbn2 forearms was significantly increased by two-fold over wildtype (p = 0.003; Fig 7B). Analysis of Fbn2-/-; Bmp7+/- forelimbs showed that the amount of fat and muscle on serial digital cross sections returned to normal wildtype levels (Fig 7B). This genetic approach provided further evidence that activated BMP signaling caused the Fbn2 myopathy, including both the reduction in muscle mass and the increase in fat that infiltrates the forelimb muscle.

Bottom Line: These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy.In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development.New evidence presented here suggests that fibrillin-2 can sequester BMP complexes in a latent state.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America; Shriners Hospital for Children, Portland, Oregon, United States of America.

ABSTRACT
Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin-2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 mice (on a 129/Sv background) are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that fibrillin-2 can sequester BMP complexes in a latent state.

No MeSH data available.


Related in: MedlinePlus