Development of antisense-mediated myostatin knockdown for the treatment of insulin resistance

Abstract Myostatin is a negative regulator of muscle mass and its inhibition represents promising strategy for the treatment disorders type 2 diabetes. However, there currently no clinically effective myostatin inhibitor, therefore novel methods are required. We evaluated use antisense phosphorodiamidate morpholino oligomers (PMO) to reduce expression in skeletal measured their effects on glucose uptake. C57/Bl6 mice received intramuscular or intravenous injections anti-myostatin PMOs. Repeated administration lead reduction transcript levels (~ 20–40%), an increase chow high-fat diet (HFD)-fed mice, but insulin-stimulated uptake was reduced PMO-treated muscles HFD-fed mice. Five weekly administrations 100 nmol PMO did not expression, had significant physiological effects. Unexpectedly, exon skipping were higher after HFD- than chow-fed These results suggest that modest PMO-induced sufficient induce mass, greater degree may be required improve