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CHIP protects against cardiac pressure overload through regulation of AMPK.


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 ? 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 ? 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.

SUBMITTER: Schisler JC 

PROVIDER: S-EPMC3726173 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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CHIP protects against cardiac pressure overload through regulation of AMPK.

Schisler Jonathan C JC   Rubel Carrie E CE   Zhang Chunlian C   Lockyer Pamela P   Cyr Douglas M DM   Patterson Cam C  

The Journal of clinical investigation 20130725 8


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  ...[more]

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