title: A novel bone morphogenetic protein 2 mutant mouse, nBmp2NLS(tm), displays impaired intracellular Ca2+ handling in skeletal muscle.
abstract: 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 (nBmp2NLS(tm)) 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 nBmp2NLS(tm) 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 Ca(2+) from the cytoplasm to the sarcoplasmic reticulum by sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), and enzyme activity assays revealed that SERCA activity in skeletal muscle from nBmp2NLS(tm) mice was reduced to approximately 80% of wild type. These results suggest that nBMP2 plays a role in the establishment or maintenance of intracellular Ca(2+) transport pathways in skeletal muscle.
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bridgewater
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Mayo
authors.affiliation: Department of Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Bradley G
authors.initials: BG
authors.lastname: Evanson
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Whitt
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Spencer A
authors.initials: SA
authors.lastname: Dean
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Yates
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Devin N
authors.initials: DN
authors.lastname: Holden
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Alina D
authors.initials: AD
authors.lastname: Schmidt
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Fox
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Saroj
authors.initials: S
authors.lastname: Dhunghel
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Steed
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Adam
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Nichols
authors.affiliation: Department of Microbiology and Molecular Biology, Brigham Young University, 775-A WIDB, Provo, UT 84602, USA.
authors.forename: Sampath K
authors.initials: SK
authors.lastname: Loganathan
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Barrow
authors.affiliation: Department of Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Hancock
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D051379:Mice; D009126:Muscle Relaxation / Q000235:genetics*; D018482:Muscle, Skeletal / Q000502:physiology; D009154:Mutation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium