A Novel Bone Morphogenetic Protein 2 Mutant Mouse, nBmp2NLStm, Displays Impaired Intracellular Ca2+ Handling in Skeletal Muscle

We recently reported a novel form of BMP2, designated nBMP2, which is translated from an alternative downstream start codon and is localized to the nucleus rather than secreted from the cell. To examine the function of nBMP2 in the nucleus, we engineered a gene-targeted mutant mouse model (nBmp2NLStm) in which nBMP2 cannot be translocated to the nucleus. Immunohistochemistry demonstrated the presence of nBMP2 staining in the myonuclei of wild type but not mutant skeletal muscle. The nBmp2NLStm mouse exhibits altered function of skeletal muscle as demonstrated by a significant increase in the time required for relaxation following a stimulated twitch contraction. Force frequency analysis showed elevated force production in mutant muscles compared to controls from 10 to 60 Hz stimulation frequency, consistent with the mutant muscle's reduced ability to relax between rapidly stimulated contractions. Muscle relaxation after contraction is mediated by the active transport of Ca2+ from the cytoplasm to the sarcoplasmic reticulum by sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and enzyme activity assays revealed that SERCA activity in skeletal muscle from nBmp2NLStm mice was reduced to approximately 80% of wild type. These results suggest that nBMP2 plays a role in the establishment or maintenance of intracellular Ca2+ transport pathways in skeletal muscle.

• Publication year

  2013

• Venue

  BioMed Research International

• Publication date

  2013-11-28

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1155/2013/125492PMID 24369527PMCID 3863484
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Ryanodine receptor channelopathies

  2010cited by this paper
• Effects of bone morphogenetic protein 2 on Id expression and neuroblastoma cell differentiation.

  2010influential reference
• BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs

  2010influential reference
• Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.

  2010cited by this paper
• Nuclear variants of bone morphogenetic proteins

  2010cited by this paper
• BMP-2 and TGF-β Stimulate Expression of β1,3-Glucuronosyl Transferase 1 (GlcAT-1) in Nucleus Pulposus Cells Through AP1, TonEBP, and Sp1: Role of MAPKs

  2009influential reference
• Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways.

  2009influential reference
• Spemann's organizer and the self-regulation of embryonic fields.

  2009cited by this paper
• Calcium-induced calcium release in skeletal muscle.

  2009cited by this paper
• In the limb AER Bmp2 and Bmp4 are required for dorsal-ventral patterning and interdigital cell death but not limb outgrowth.

  2009cited by this paper
• Bone morphogenetic protein signaling in limb outgrowth and patterning

  2007cited by this paper
• Developmental and adult phenotyping directly from mutant embryonic stem cells

  2007cited by this paper
• Contraction-mediated phosphorylation of AMPK is lower in skeletal muscle of adenylate kinase-deficient mice.

  2006cited by this paper
• Expression of bone morphogenetic protein 2 in breast cancer cells inhibits hypoxic cell death.

  2005influential reference
• Simple and highly efficient BAC recombineering using galK selection

  2005cited by this paper
• Calcium Signaling Protocols

  2005influential reference
• BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system.

  2005cited by this paper
• 31P-NMR observation of free ADP during fatiguing, repetitive contractions of murine skeletal muscle lacking AK1.

  2005cited by this paper
• Mouse phenotypes: a handbook of mutation analysis.

  2005cited by this paper
• Biophysical Comparison of BMP-2, ProBMP-2, and the Free Pro-peptide Reveals Stabilization of the Pro-peptide by the Mature Growth Factor*

  2005cited by this paper
• Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice.

  2005cited by this paper
• Bone Morphogenetic Proteins

  2004influential reference
• Protein Kinase C-independent Activation of Protein Kinase D Is Involved in BMP-2-induced Activation of Stress Mitogen-activated Protein Kinases JNK and p38 and Osteoblastic Cell Differentiation*

  2004influential reference
• Function of bone morphogenetic protein signaling during mouse development.

  2003influential reference
• BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo.

  2002influential reference
• From mono- to oligo-Smads: The heart of the matter in TGF- (cid:1) signal transduction

  2002influential reference
• From mono- to oligo-Smads: the heart of the matter in TGF-beta signal transduction.

  2002cited by this paper
• Action range of BMP is defined by its N-terminal basic amino acid core.

  2002cited by this paper
• Bone Morphogenetic Protein (BMP)-2 Induces Apoptosis in Human Myeloma Cells

  2002influential reference
• Recombineering: a powerful new tool for mouse functional genomics

  2001cited by this paper
• The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease

  2000cited by this paper
• Measurement of Ca(2+)-ATPase activity (in PMCA and SERCA1).

  1999cited by this paper
• Regulation of Bone Morphogenetic Protein Activity by Pro Domains and Proprotein Convertases

  1999cited by this paper
• Targeting genes for self-excision in the germ line.

  1999cited by this paper
• Calcium Signaling Protocols

  1999cited by this paper
• Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development.

  1996influential reference
• Bone morphogenetic proteins: multifunctional regulators of vertebrate development.

  1996cited by this paper
• Mutations in the gene–encoding SERCA1, the fast–twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease

  1996cited by this paper
• Characterization of cDNA and genomic DNA encoding SERCA1, the Ca(2+)-ATPase of human fast-twitch skeletal muscle sarcoplasmic reticulum, and its elimination as a candidate gene for Brody disease.

  1995cited by this paper
• Ca2+ homeostasis in Brody's disease. A study in skeletal muscle and cultured muscle cells and the effects of dantrolene an verapamil.

  1994cited by this paper
• Bone morphogenetic proteins.

  1989cited by this paper
• Novel regulators of bone formation: molecular clones and activities.

  1988cited by this paper
• Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes

  1988cited by this paper
• Muscle contracture induced by exercise. A syndrome attributable to decreased relaxing factor.

  1969cited by this paper
• Bone: Formation by Autoinduction

  1965cited by this paper
• Ca 2+ Homeostasis in Brody's Disease A Study in Skeletal Muscle and Cultured Muscle Cells and the Effects of Dantrolene and Verapamil beneficial and on

  year unknowncited by this paper

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  2019cites this paper
• Histomorphometry of ectopic mineralization using undecalcified frozen bone sections

  2018influential citation
• The BMP2 nuclear variant, nBMP2, is expressed in mouse hippocampus and impacts memory

  2017cites this paper
• Mitogen and Morphogen Signaling Dysregulation: Pathophysiological Influence in Pancreatic Cancer and Alzheimer’s Disease

  2016cites this paper
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  2015cites this paper