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.
View: Text | PDF
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

×

Figure 1

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

Options: View larger image (or click on image) Download as PowerPoint
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.