Absence of synemin in mice causes structural and functional abnormalities in heart. (January 2018)

• Record Type: Journal Article
• Authors: García-Pelagio, Karla P.; Chen, Ling; Joca, Humberto C.; Ward, Christopher; Jonathan Lederer, W.; Bloch, Robert J.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 114(2018)
• Page Start: 354
• Page End: 363
• Publication Date: 2018-01
• Subjects: Costameres -- Intermediate filament -- AKAPs -- Hypertrophic and dilated cardiomyopathy -- Muscular dystrophy; + dP/dt maximal rate of left ventricular pressure rise -- -dP/dt maximal rate of left ventricular pressure fall -- + dP/dt-EDP end-diastolic pressure adjusted maximal rate of left ventricular pressure rise -- AKAP A-kinase anchoring protein -- AKT protein kinase B also known as Akt -- BP blood pressure -- BW body weight -- CM cardiomyopathy -- CO cardiac output -- CREB cAMP response element-binding protein -- DCM dilated cardiomyopathy -- E/A the ratio of the early (E) to late (A) filling velocities of the left ventricle -- ECM extracellular matrix -- EDP end-diastolic pressure -- EDPVR the slope of the end-diastolic pressure-volume relationship -- EF ejection fraction -- ERK 1/2 extracellular signal-regulated kinase 1/2 -- ESP end-systolic pressure -- Ea effective arterial elastance -- Ees the slope of left ventricular end-systolic pressure-volume relationship -- FS fractional shortening -- HCM hypertrophic cardiomyopathy -- HR heart rate -- IFs intermediate filaments -- IVC inferior vena cava -- LV left ventricle or left ventricular -- LVDd LV end-diastolic dimension -- LVDs LV end-systolic dimension -- MAPKs mitogen-activated protein kinases -- MBP mean blood pressure -- PV Pressure-volume -- PKA RII protein kinase A subunit II -- PRSW preload recruitable stroke work -- Pes pressure end-systolic -- SL sarcomere length -- SV stroke volume -- SW stroke work -- synm −/− synemin-null -- Tau isovolumic relaxation time constant -- WT wild type mice; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2017.12.005
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Cardiomyopathies have been linked to changes in structural proteins, including intermediate filament (IF) proteins located in the cytoskeleton. IFs associate with the contractile machinery and costameres of striated muscle and with intercalated disks in the heart. Synemin is a large IF protein that mediates the association of desmin with Z-disks and stabilizes intercalated disks. It also acts as an A-kinase anchoring protein (AKAP). In murine skeletal muscle, the absence of synemin causes a mild myopathy. Here, we report that the genetic silencing of synemin in mice (synm −/−) causes left ventricular systolic dysfunction at 3 months and 12–16 months of age, and left ventricular hypertrophy and dilatation at 12–16 months of age. Isolated cardiomyocytes showed alterations in calcium handling that indicate defects intrinsic to the heart. Although contractile and costameric proteins remained unchanged in the old synm −/− hearts, we identified alterations in several signaling proteins (PKA-RII, ERK and p70S6K) critical to cardiomyocyte function. Our data suggest that synemin plays an important regulatory role in the heart and that the consequences of its absence are profound. Highlights: Synm −/− cardiac muscle shows structural and functional changes associated with hypertrophic and dilated cardiomyopathies. Cardiomyocytes isolated from synm −/− heart have altered calcium transients. Changes in signaling molecules, PKA-RII, ERK and p70S6K, occur in synm −/− heart.