title: Altered functional differentiation of mesoangioblasts in a genetic myopathy.
abstract: Mutations underlying genetic cardiomyopathies might affect differentiation commitment of resident progenitor cells. Cardiac mesoangioblasts (cMabs) are multipotent progenitor cells resident in the myocardium. A switch from cardiac to skeletal muscle differentiation has been recently described in cMabs from β-sarcoglycan-null mice (βSG(-/-)), a murine model of genetic myopathy with early myocardial involvement. Although complementation with βSG gene was inconsequential, knock-in of miRNA669a (missing in βSG(-/-) cMabs) partially rescued the mutation-induced molecular phenotype. Here, we undertook a detailed evaluation of functional differentiation of βSG(-/-) cMabs and tested the effects of miRNA669a-induced rescue in vitro. To this end, cMabs were compared with neonatal cardiomyocytes (CMs) and skeletal muscle C2C12 cells, representative of cardiac and skeletal muscle respectively. Consistent with previous data on molecular patterns, electrophysiological and Ca(2+)-handling properties of βSG(-/-) cMabs were closer to C2C12 cells than to CM ones. Nevertheless, subtler aspects, including action potential contour, Ca(2+)-spark properties and RyR isoform expression, distinguished βSG(-/-) cMabs from C2C12 cells. Contrary to previous reports, wild-type cMabs failed to show functional differentiation towards either cell type. Knock-in of miRNA669a in βSG(-/-) cMabs rescued the wild-type functional phenotype, i.e. it completely prevented development of skeletal muscle functional responses. We conclude that miRNA669a expression, ablated by βSG deletion, may prevent functional differentiation of cMabs towards the skeletal muscle phenotype.
authors: Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors: Claudia
authors: C
authors: Altomare
authors: Lucio
authors: L
authors: Barile
authors: Marcella
authors: M
authors: Rocchetti
authors: Luca
authors: L
authors: Sala
authors: Stefania
authors: S
authors: Crippa
authors: Maurilio
authors: M
authors: Sampaolesi
authors: Antonio
authors: A
authors: Zaza
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004594:Electrophysiology; D006321:Heart / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D049031:Sarcoglycans / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D049031:Sarcoglycans; D002118:Calcium
references: Circ Res. 2004 Oct 29;95(9):911-21
references: 15472116
references: Circulation. 2007 Feb 20;115(7):896-908
references: 17283259
references: Curr Genomics. 2009 May;10(3):184-93
references: 19881911
references: Am J Physiol Cell Physiol. 2007 Sep;293(3):C1073-81
references: 17376815
references: Curr Protoc Stem Cell Biol. 2007 Dec;Chapter 2:Unit 2B.1
references: 18785178
references: J Physiol. 2008 Jan 15;586(2):441-57
references: 18006577
references: Mol Cell. 2000 Jan;5(1):141-51
references: 10678176
references: PLoS One. 2008;3(11):e3644
references: 18982068
references: Cardiovasc Res. 2009 Sep 1;83(4):707-16
references: 19457891
references: J Cell Biol. 2011 Jun 27;193(7):1197-212
references: 21708977
references: Cell. 2003 Sep 19;114(6):763-76
references: 14505575
references: J Physiol. 2001 Dec 1;537(Pt 2):379-89
references: 11731572
references: Nat Cell Biol. 2007 Mar;9(3):255-67
references: 17293855
references: J Physiol. 2000 Jun 1;525 Pt 2:499-507
references: 10835050
references: J Physiol. 1994 Sep 1;479 ( Pt 2):265-79
references: 7799226
references: J Pathol. 2012 Jan;226(2):200-18
references: 21989954
references: Physiol Rev. 2002 Apr;82(2):291-329
references: 11917091
references: Nature. 2006 Nov 30;444(7119):574-9
references: 17108972
references: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10440-5
references: 12928492
references: J Mol Cell Cardiol. 2010 Feb;48(2):415-23
references: 19837079
references: Biophys J. 2001 Dec;81(6):3216-30
references: 11720987
references: Cell Death Differ. 2008 Sep;15(9):1417-28
references: 18497758
references: Development. 2002 Jun;129(11):2773-83
references: 12015303
references: Acta Pharmacol Sin. 2006 Jul;27(7):791-8
references: 16787561
references: Nat Cell Biol. 2005 May;7(5):525-30
references: 15834406
references: J Gen Physiol. 1996 Nov;108(5):405-19
references: 8923266
references: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5235-40
references: 17360329
references: Basic Res Cardiol. 2010 Nov;105(6):737-49
references: 20652277
references: Biophys J. 2000 Nov;79(5):2509-25
references: 11053126
references: Pharmacol Ther. 1998 Mar;77(3):183-202
references: 9576627