TY - JOUR
T1 - Liver Kinase B1 complex acts as a novel modifier of myofilament function and localizes to the Z-disk in cardiac myocytes
AU - Behunin, Samantha M.
AU - Lopez-Pier, Marissa A.
AU - Mayfield, Rachel M.
AU - Danilo, Christiane A.
AU - Lipovka, Yulia
AU - Birch, Camille
AU - Lehman, Sarah
AU - Tardiff, Jil C.
AU - Gregorio, Carol C.
AU - Konhilas, John P.
N1 - Funding Information:
Support was also received from the Sarver Heart Center at the University of Arizona and the Steven M. Gootter Foundation . Mass spectrometry and proteomics data were acquired by the Arizona Proteomics Consortium supported by NIEHS grant ES06694 to the SWEHSC, NIH/NCI grant CA023074 to the UA Cancer Center and by the BIO5 Institute of the University of Arizona . The Thermo Fisher LTQ Orbitrap Velos mass spectrometer was provided by grant 1S10 RR028868-01 from NIH/NCRR .
Funding Information:
This work was supported by National Institutes of Health grant HL098256 , a National Mentored Research Science Development Award ( K01 AR052840 ) and Independent Scientist Award ( K02 HL105799 ) from the NIH to J.P.K., and an Interdisciplinary Training Grant in Cardiovascular Sciences ( HL007249 ). NIH grants HL108625 and HL123078 (to C.C.G.) and HL075619 (to J.C.T) also provided support for this work.
Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Contractile perturbations downstream of Ca2+ binding to troponin C, the so-called sarcomere-controlled mechanisms, represent the earliest indicators of energy remodeling in the diseased heart [1]. Central to cellular energy "sensing" is the adenosine monophosphate-activated kinase (AMPK) pathway, which is known to directly target myofilament proteins and alter contractility [2-6]. We previously showed that the upstream AMPK kinase, LKB1/MO25/STRAD, impacts myofilament function independently of AMPK [5]. Therefore, we hypothesized that the LKB1 complex associated with myofilament proteins and that alterations in energy signaling modulated targeting or localization of the LKB1 complex to the myofilament. Using an integrated strategy of myofilament mechanics, immunoblot analysis, co-immunoprecipitation, mass spectroscopy, and immunofluorescence, we showed that 1) LKB1 and MO25 associated with myofibrillar proteins, 2) cellular energy stress re-distributed AMPK/LKB1 complex proteins within the sarcomere, and 3) the LKB1 complex localized to the Z-Disk and interacted with cytoskeletal and energy-regulating proteins, including vinculin and ATP Synthase (Complex V). These data represent a novel role for LKB1 complex proteins in myofilament function and myocellular "energy" sensing in the heart.
AB - Contractile perturbations downstream of Ca2+ binding to troponin C, the so-called sarcomere-controlled mechanisms, represent the earliest indicators of energy remodeling in the diseased heart [1]. Central to cellular energy "sensing" is the adenosine monophosphate-activated kinase (AMPK) pathway, which is known to directly target myofilament proteins and alter contractility [2-6]. We previously showed that the upstream AMPK kinase, LKB1/MO25/STRAD, impacts myofilament function independently of AMPK [5]. Therefore, we hypothesized that the LKB1 complex associated with myofilament proteins and that alterations in energy signaling modulated targeting or localization of the LKB1 complex to the myofilament. Using an integrated strategy of myofilament mechanics, immunoblot analysis, co-immunoprecipitation, mass spectroscopy, and immunofluorescence, we showed that 1) LKB1 and MO25 associated with myofibrillar proteins, 2) cellular energy stress re-distributed AMPK/LKB1 complex proteins within the sarcomere, and 3) the LKB1 complex localized to the Z-Disk and interacted with cytoskeletal and energy-regulating proteins, including vinculin and ATP Synthase (Complex V). These data represent a novel role for LKB1 complex proteins in myofilament function and myocellular "energy" sensing in the heart.
KW - Contractility
KW - Liver Kinase B1 (LKB1)
KW - Myofibril
KW - Myofilament
KW - Vinculin
KW - Z-disk
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U2 - 10.1016/j.abb.2016.03.012
DO - 10.1016/j.abb.2016.03.012
M3 - Article
C2 - 26971467
AN - SCOPUS:84962246238
VL - 601
SP - 32
EP - 41
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
SN - 0003-9861
ER -