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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

Forelimb contractures, reduced muscle mass and altered muscle morphology in P0 Fbn2  mice.(A)Fbn2  forelimb contractures from P0 to P8. (B) Representative H&E stained P0 forearm cross sections from the same approximate position in the forearm. The cross sections are composites of multiple micrographs. (C) Left: Quantitation of total forearm muscle mass dissected from Fbn2+/+, Fbn2+/-, and Fbn2-/- animals. The ratio of total muscle mass/total body weight was normalized to wildtype. N = the number of animals used. Right: 50% reduction of myofibers, counted on all micrographs forming composite cross sections of Fbn2  forearm muscle compared to wildtype. N = the number of animals used. (D) H&E stained sections (left) of Fbn2  forearm muscle at P0 with increased numbers of myofibers with central nuclei (arrows) compared to wildtype and quantitation of myofibers with central nuclei (right). When myofibers in all muscle groups were counted for Fig 1C, a second count was performed for myofibers with central nuclei. Numbers were added and divided by the total number of myofibers (obtained for 1C) to obtain percentage with central nuclei. N = the number of animals used. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 50 μm.
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pgen.1005340.g001: Forelimb contractures, reduced muscle mass and altered muscle morphology in P0 Fbn2 mice.(A)Fbn2 forelimb contractures from P0 to P8. (B) Representative H&E stained P0 forearm cross sections from the same approximate position in the forearm. The cross sections are composites of multiple micrographs. (C) Left: Quantitation of total forearm muscle mass dissected from Fbn2+/+, Fbn2+/-, and Fbn2-/- animals. The ratio of total muscle mass/total body weight was normalized to wildtype. N = the number of animals used. Right: 50% reduction of myofibers, counted on all micrographs forming composite cross sections of Fbn2 forearm muscle compared to wildtype. N = the number of animals used. (D) H&E stained sections (left) of Fbn2 forearm muscle at P0 with increased numbers of myofibers with central nuclei (arrows) compared to wildtype and quantitation of myofibers with central nuclei (right). When myofibers in all muscle groups were counted for Fig 1C, a second count was performed for myofibers with central nuclei. Numbers were added and divided by the total number of myofibers (obtained for 1C) to obtain percentage with central nuclei. N = the number of animals used. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 50 μm.

Mentions: On 129/Sv background, Fbn2 mice are viable and fertile, but are born with contractures of their forelimbs which disappear within the first week of postnatal life [11]. Because of the similarity between the contractures found in Fbn2 mice and in humans with CCA, Fbn2 mice are a model for CCA. Daily inspection of the Fbn2 forelimbs during the first week of life revealed that the contractures were most severe between birth and P2 and slowly resolved between P3 and P8 (Fig 1A).


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)

Forelimb contractures, reduced muscle mass and altered muscle morphology in P0 Fbn2  mice.(A)Fbn2  forelimb contractures from P0 to P8. (B) Representative H&E stained P0 forearm cross sections from the same approximate position in the forearm. The cross sections are composites of multiple micrographs. (C) Left: Quantitation of total forearm muscle mass dissected from Fbn2+/+, Fbn2+/-, and Fbn2-/- animals. The ratio of total muscle mass/total body weight was normalized to wildtype. N = the number of animals used. Right: 50% reduction of myofibers, counted on all micrographs forming composite cross sections of Fbn2  forearm muscle compared to wildtype. N = the number of animals used. (D) H&E stained sections (left) of Fbn2  forearm muscle at P0 with increased numbers of myofibers with central nuclei (arrows) compared to wildtype and quantitation of myofibers with central nuclei (right). When myofibers in all muscle groups were counted for Fig 1C, a second count was performed for myofibers with central nuclei. Numbers were added and divided by the total number of myofibers (obtained for 1C) to obtain percentage with central nuclei. N = the number of animals used. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 50 μm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4482570&req=5

pgen.1005340.g001: Forelimb contractures, reduced muscle mass and altered muscle morphology in P0 Fbn2 mice.(A)Fbn2 forelimb contractures from P0 to P8. (B) Representative H&E stained P0 forearm cross sections from the same approximate position in the forearm. The cross sections are composites of multiple micrographs. (C) Left: Quantitation of total forearm muscle mass dissected from Fbn2+/+, Fbn2+/-, and Fbn2-/- animals. The ratio of total muscle mass/total body weight was normalized to wildtype. N = the number of animals used. Right: 50% reduction of myofibers, counted on all micrographs forming composite cross sections of Fbn2 forearm muscle compared to wildtype. N = the number of animals used. (D) H&E stained sections (left) of Fbn2 forearm muscle at P0 with increased numbers of myofibers with central nuclei (arrows) compared to wildtype and quantitation of myofibers with central nuclei (right). When myofibers in all muscle groups were counted for Fig 1C, a second count was performed for myofibers with central nuclei. Numbers were added and divided by the total number of myofibers (obtained for 1C) to obtain percentage with central nuclei. N = the number of animals used. Error bars indicate mean ± SD, and asterisks indicate statistically significant differences (p < 0.05) between genotypes. Bars = 50 μm.
Mentions: On 129/Sv background, Fbn2 mice are viable and fertile, but are born with contractures of their forelimbs which disappear within the first week of postnatal life [11]. Because of the similarity between the contractures found in Fbn2 mice and in humans with CCA, Fbn2 mice are a model for CCA. Daily inspection of the Fbn2 forelimbs during the first week of life revealed that the contractures were most severe between birth and P2 and slowly resolved between P3 and P8 (Fig 1A).

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