miR-322 regulates insulin signaling pathway and protects against metabolic syndrome-induced cardiac dysfunction in mice

Biochim Biophys Acta. 2016 Apr;1862(4):611-621. doi: 10.1016/j.bbadis.2016.01.010. Epub 2016 Jan 13.


We identified murine miR-322, orthologous to human miR-424, as a new regulator of insulin receptor, IGF-1 receptor and sirtuin 4 mRNA in vitro and in vivo in the heart and found that miR-322/424 is highly expressed in the heart of mice. C57Bl/6N mice fed 10weeks of high fat diet (HFD) presented signs of cardiomyopathy and a stable miR-322 cardiac level while cardiac function was slightly affected in 11week-old ob/ob which overexpressed miR-322. We thus hypothesized that mmu-miR-322 could be protective against cardiac consequences of hyperinsulinemia and hyperlipidemia. We overexpressed or knocked-down mmu-miR-322 using AAV9 and monitored cardiac function in wild-type C57Bl/6N mice fed a control diet (CD) or a HFD and in ob/ob mice. The fractional shortening progressively declined while the left ventricle systolic diameter increased in HFD mice infected with an AAVcontrol or with an AAVsponge (decreasing miR-322 bioavailability) but also in ob/ob mice infected with AAVsponge. Similar observations were also found in CD-fed mice infected with AAVsponge. On the contrary over-expressing miR-322 with AAVmiR-322 was efficient in protecting the heart from HFD effects in C57Bl/6N mice. This cardioprotection could be associated with the regulation of identified targets IGF1R, INSR and CD1, a decrease in insulin signaling pathway and an enrichment of genes involved in mitochondrial function and fatty acid oxidation as demonstrated by transcriptome analysis. Altogether, these results emphasize miR-322 as a new potential therapeutic target against cardiac consequences of metabolic syndrome, which represents an increasing burden in the western countries.

Keywords: Cardiomyopathy; High fat diet; Insulin pathway; Metabolic syndrome; MicroRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dependovirus
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology
  • Genetic Vectors
  • Heart Diseases / genetics
  • Heart Diseases / metabolism*
  • Heart Diseases / pathology
  • Heart Diseases / therapy
  • Humans
  • Hyperinsulinism / genetics
  • Hyperinsulinism / metabolism
  • Hyperinsulinism / pathology
  • Hyperinsulinism / therapy
  • Hyperlipidemias / genetics
  • Hyperlipidemias / metabolism
  • Hyperlipidemias / pathology
  • Hyperlipidemias / therapy
  • Insulin / genetics
  • Insulin / metabolism*
  • Male
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / pathology
  • Metabolic Syndrome / therapy
  • Mice
  • Mice, Obese
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Rats
  • Rats, Wistar
  • Signal Transduction*
  • Transduction, Genetic


  • Dietary Fats
  • Insulin
  • MIRN322 microRNA, mouse
  • MIRN322 microRNA, rat
  • MicroRNAs