Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice

Gerhard Sengle, Valerie Carlberg, Sara F. Tufa, Noe L. Charbonneau, Silvia Smaldone, Eric J. Carlson, Francesco Ramirez, Douglas R. Keene, Lynn Sakai

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 null 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 null 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 null mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 null mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 null 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 null mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 null 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.

Original languageEnglish (US)
Article numbere1005340
JournalPLoS genetics
Volume11
Issue number6
DOIs
StatePublished - Jan 1 2015

Fingerprint

muscular diseases
Muscular Diseases
muscle
Muscles
muscles
mice
White Adipose Tissue
white adipose tissue
Forelimb
forelimbs
muscular dystrophy
Muscular Dystrophies
fat
musculoskeletal diseases
contracture
Microfibrils
mutation
Recessive Genes
defect
gene

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Sengle, G., Carlberg, V., Tufa, S. F., Charbonneau, N. L., Smaldone, S., Carlson, E. J., ... Sakai, L. (2015). Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. PLoS genetics, 11(6), [e1005340]. https://doi.org/10.1371/journal.pgen.1005340

Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. / Sengle, Gerhard; Carlberg, Valerie; Tufa, Sara F.; Charbonneau, Noe L.; Smaldone, Silvia; Carlson, Eric J.; Ramirez, Francesco; Keene, Douglas R.; Sakai, Lynn.

In: PLoS genetics, Vol. 11, No. 6, e1005340, 01.01.2015.

Research output: Contribution to journalArticle

Sengle, G, Carlberg, V, Tufa, SF, Charbonneau, NL, Smaldone, S, Carlson, EJ, Ramirez, F, Keene, DR & Sakai, L 2015, 'Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice', PLoS genetics, vol. 11, no. 6, e1005340. https://doi.org/10.1371/journal.pgen.1005340
Sengle G, Carlberg V, Tufa SF, Charbonneau NL, Smaldone S, Carlson EJ et al. Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. PLoS genetics. 2015 Jan 1;11(6). e1005340. https://doi.org/10.1371/journal.pgen.1005340
Sengle, Gerhard ; Carlberg, Valerie ; Tufa, Sara F. ; Charbonneau, Noe L. ; Smaldone, Silvia ; Carlson, Eric J. ; Ramirez, Francesco ; Keene, Douglas R. ; Sakai, Lynn. / Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. In: PLoS genetics. 2015 ; Vol. 11, No. 6.
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