Journal
LIFE SCIENCES
Volume 98, Issue 2, Pages 75-82Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2014.01.006
Keywords
Contractile function; AMPK; Troponin I
Funding
- American Heart Association SDG [0835169N, 12GRNT 11620029]
- American Diabetes Association Basic Sciences Grant [1-11-BS-92]
- National Natural Science Foundation of China [31171121]
- Major International (Regional) Joint Research Project [2008DFA31140, 2010DFA32660]
- Guangdong Natural Science Fund [10251008002000002, S2011010005836]
- Chinese Science and Technology Support Program [2011BAI11B22]
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Aims: The specific role of AMPK alpha 1 or AMPK alpha 2 in mediating cardiomyocyte contractile function remains elusive. The present study investigated how AMPK activation modulates the contractility of isolated cardiomyocytes. Main methods: Mechanical properties and intracellular Ca2+ properties were measured in isolated cardiomyocytes. The stress signaling was evaluated using western blot and immunoprecipitation analysis. Key findings: AMPK activator, A-769662 induced maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt), peak height and peak shortening (PS) amplitude in both WT and AMPK alpha 2 KO cardiomyocytes, but did not affect time-to-90% relengthening (TR90). AMPK KD cardiomyocytes demonstrated contractile dysfunction compared with cardiomyocytes from WT and AMPK alpha 2 KO hearts. However, the rise of intracellular Ca2+ levels as well as intracellular ATP levels has no significant difference among WT, AMPK alpha 2 KO and AMPK KD groups with and without the presence of A-769662. Besides, WT, AMPK alpha 2 KO and AMPK MD group displayed a phosphorylated AMPK and downstream acetyl-CoA carboxylase (ACC) phosphorylation. Interestingly, A-769662 also triggered troponin I (cTnI) phosphorylation at Ser(149) site which is related to contractility of cardiomyocytes. Furthermore, the immunoprecipitation analysis revealed that AMPK alpha 1 of cardiomyocytes was phosphorylated by A-769662. Significance: This is the first study illustrating that activation of AMPK plays a significant role in mediating the contractile function of cardiomyocytes using transgenic animal models. AMPK activator facilitates the contractility of cardiomyocytes via activating AMPK alpha 1 catalytic subunit. The phosphorylation of cTnI by AMPK could be a factor attributing to the regulation of contractility of cardiomyocytes. (c) 2014 Elsevier Inc. All rights reserved,
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