期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1865, 期 10, 页码 2736-2752出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2019.07.003
关键词
Exercise; Detraining; IGF1; mTORC2; PKC alpha; FRC delta
资金
- Department of Biotechnology, Government of India [BT-PR3709/BRB/10/980/2011, BT/PR7016/NNT/28/641/2012]
- Department of Science and Technology, Government of India [SB/SO/HS-148/2013]
- DST -FIST program, Government of India [SR/FST/LS-II/2017/110]
- Indian Council of Medical Research [3/1/2(9)/CVD/2018-NCD-II]
Altered cardiac adaptation of physiologically hypertrophied heart during detraining remained obscure for long time. We had previously reported the switching of protein kinase C (PKC) isoforms (-alpha to -delta) associated with functional deterioration of heart at detraining in mice undergone swim exercise. Here we report that, myocardium targeted overexpression of insulin-like growth factor 1 (IGF1) and knockdown of insulin-like growth factor 1 receptor (IGF1R) during detraining and exercise respectively altered the activation of PKCs and eventual cardiac condition. Moreover, downregulation of mammalian target of rapamycin complex 2 (mTORC2) was recorded in both IGF1R knockdown or detraining groups. Additionally, knocking down of mTORC2 during exercise exhibited impaired cardiac condition. Interestingly, significantly increased interactions of mTORC2 with both PKC alpha and delta was recorded exclusively in exercise group. This interaction resulted into hydrophobic motif phosphorylation of both PKCs (Serine657-PKC alpha; Serine662-PKC delta). Serine phosphorylation on one hand activated PKC alpha mediated cell survival and on the other hand alleviated the apoptotic activity of PKC delta during exercise. Mutation of Serine662 of PKC delta in exercised mice showed higher Tyrosine311 phosphorylation with increased apoptotic load similar to that in detrained animals. These observations confirmed that differential and conditional activation of PKCs depend upon IGF1 induced mTORC2 activation. Furthermore, blocking of PKC alpha resulted in activated p53 which in turn repressed IGF1 expression during swim, mimicking the condition of detrained heart. In conclusion, this is the first report to unravel the intricate molecular mechanism of switching a physiologically hypertrophied heart to a pathologically hypertrophied heart during exercise withdrawal.
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