CHIP protects against cardiac pressure overload through regulation of AMPK
Jonathan C. Schisler, Carrie E. Rubel, Chunlian Zhang, Pamela Lockyer, Douglas M. Cyr, Cam Patterson
Jonathan C. Schisler, Carrie E. Rubel, Chunlian Zhang, Pamela Lockyer, Douglas M. Cyr, Cam Patterson
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Research Article Cardiology

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 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 1

Pressure overload-induced cardiac hypertrophy in Chip–/– mice.

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Pressure overload-induced cardiac hypertrophy in Chip–/– mice. (A) Ind...
(A) Indirect immunofluorescence images of CHIP expression (magenta) and nuclei (green) in mouse heart. The arrow indicates sarcomere localization; dashed areas indicate nuclear localization (white). Scale bar: 50 μm. (B) Survival curves after TAB surgery in wild-type or Chip–/– mice (n = 12 and 20, respectively). (C) Hematoxylin and eosin–stained whole heart sections from the indicated conditions. Scale bar: 1 mm. (D) Heart weight normalized to tibia length (mg/mm; n = 3 and 6 male and female wild-type sham mice, respectively; n = 5 and 8 male and female wild-type TAB mice, respectively; n = 3 and 5 male and female Chip–/– sham mice, respectively; n = 8 male and female Chip–/– TAB mice, respectively; P < 0.01 across all sexes and genotypes, sham vs. TAB; ††P < 0.01 sex-matched wild-type vs. Chip–/– mice). (E) Fractional shortening (%) after sham or TAB surgery (n = 6 and 7 for sham and 8 and 6 for TAB in wild-type and Chip–/– mice, respectively; †††P < 0.001 vs. all other groups). (F) Representative histological staining of whole heart sections from wild-type and Chip–/– mice. Lectin images represent 25 areas from 4 mice per condition. In Masson trichrome images, numbers represent percentage interstitial fibrosis (n = 13). ###P < 0.001 TAB vs. sham; †††P < 0.001 wild-type vs. Chip–/–. Arrows indicate intercellular and intracellular regions void of tissue. Scale bar: 100 μm.