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CHIP protects against cardiac pressure overload through regulation of AMPK
Jonathan C. Schisler, … , Douglas M. Cyr, Cam Patterson
Jonathan C. Schisler, … , Douglas M. Cyr, Cam Patterson
Published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3588-3599. https://doi.org/10.1172/JCI69080.
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Research Article Cardiology Article has an altmetric score of 13

CHIP protects against cardiac pressure overload through regulation of AMPK

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Abstract

Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in Chip–/– mice resulted in robust hypertrophy and decreased cardiac function and energy generation stemming from a failure to activate AMPK. Mechanistically, CHIP promoted LKB1-mediated phosphorylation of AMPK, increased the specific activity of AMPK, and was necessary and sufficient for stress-dependent activation of AMPK. CHIP-dependent effects on AMPK activity were accompanied by conformational changes specific to the α subunit, both in vitro and in vivo, identifying AMPK as the first physiological substrate for CHIP chaperone activity and establishing a link between cardiac proteolytic and metabolic pathways.

Authors

Jonathan C. Schisler, Carrie E. Rubel, Chunlian Zhang, Pamela Lockyer, Douglas M. Cyr, Cam Patterson

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Figure 4

Analysis of the CHIP-AMPK interaction.

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Analysis of the CHIP-AMPK interaction.
(A) Immunoblot analysis from CHIP...
(A) Immunoblot analysis from CHIP or control (IgG) immunoprecipitations in wild-type and Chip–/– heart lysates. (B) Immunoprecipitations of reactions containing recombinant CHIP, AMPKα1β1γ1, AMPKα2β1γ1, or combined proteins, subsequently immunoblotted with the indicated antibodies. (C) Densitometry of AMPKα-T172 phosphorylation (pT172) and AMPK activity measured by SAMS phosphorylation (pSAMS) in reactions containing combinations of proteins as indicated. Relative pT172 was normalized to total AMPKα. Data are represented by the mean ± SEM from 3 independent experiments (2-way ANOVA, †P < 0.05, ††P < 0.01,comparing time; ‡P < 0.05, ‡‡P < 0.01, and ‡‡‡P < 0.0001, comparing the presence of CHIP; t test, *P < 0.05 and **P < 0.01, comparing the presence of CHIP per time point). (D) Activated pAMPKα1β1γ1 (pα1, green) and pAMPKα2β1γ1 (pα2, blue) activity in the absence or presence of CHIP (+C) measured by SAMS phosphorylation (represented by mean ± SEM from 3 independent experiments) (ANOVA post-hoc test, ***P < 0.001 comparing all pairs of conditions). Values were normalized to control conditions (0.5 hours in the absence of CHIP); “#” indicates activity measurements not significantly above background. The samples were also immunoblotted for total AMPKα1 or AMPKα2 from the indicated conditions. (E) AMPK activity measured by pSAMS (represented by mean ± SEM from 3 biological replicates) using reactions containing either activated pAMPKα1β1γ1 (green) or pAMPKα2β1γ1 (blue) mixed with increasing amounts of recombinant CHIP. Dashed green and blue lines represent baseline activities of pα1β1γ1 and pα2β1γ1, respectively.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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