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

Eilers, W; Cleasby, M; Foster, K

Abstract

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

Citation

Eilers, W., Cleasby, M., & Foster, K. (2021). Development of antisense-mediated myostatin knockdown for the treatment of insulin resistance. Scientific Reports, 11(1), https://doi.org/10.1038/s41598-021-81222-7

• Journal Article Type: Article
• Acceptance Date: Dec 23, 2020
• Publication Date: 2021
• Deposit Date: Dec 10, 2021
• Publicly Available Date: Dec 10, 2021
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 1
• DOI: https://doi.org/10.1038/s41598-021-81222-7
• Keywords: GROSS MUSCLE HYPERTROPHY; SKELETAL-MUSCLE; EXPRESSION; GENE; MUTATION; MICE; SENSITIVITY; OLIGOMERS; EFFICACY; MASS
• Public URL: https://rvc-repository.worktribe.com/output/1553057