HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury
Document Type
Journal Article
Publication Title
Skeletal Muscle
ISSN
2044-5040
Volume
8
Issue
1
First Page
35
Last Page
35
PubMed ID
30424786
Publisher
Springer Nature
School
School of Medical and Health Sciences
RAS ID
28027
Abstract
BACKGROUND: In muscular dystrophy and old age, skeletal muscle repair is compromised leading to fibrosis and fatty tissue accumulation. Therefore, therapies that protect skeletal muscle or enhance repair would be valuable medical treatments. Hypoxia-inducible factors (HIFs) regulate gene transcription under conditions of low oxygen, and HIF target genes EPO and VEGF have been associated with muscle protection and repair. We tested the importance of HIF activation following skeletal muscle injury, in both a murine model and human volunteers, using prolyl hydroxylase inhibitors that stabilize and activate HIF.
METHODS: Using a mouse eccentric limb injury model, we characterized the protective effects of prolyl hydroxylase inhibitor, GSK1120360A. We then extended these studies to examine the impact of EPO modulation and infiltrating immune cell populations on muscle protection. Finally, we extended this study with an experimental medicine approach using eccentric arm exercise in untrained volunteers to measure the muscle-protective effects of a clinical prolyl hydroxylase inhibitor, daprodustat.
RESULTS: GSK1120360A dramatically prevented functional deficits and histological damage, while accelerating recovery after eccentric limb injury in mice. Surprisingly, this effect was independent of EPO, but required myeloid HIF1α-mediated iNOS activity. Treatment of healthy human volunteers with high-dose daprodustat reduced accumulation of circulating damage markers following eccentric arm exercise, although we did not observe any diminution of functional deficits with compound treatment.
CONCLUSION: The results of these experiments highlight a novel skeletal muscle protective effect of prolyl hydroxylase inhibition via HIF-mediated expression of iNOS in macrophages. Partial recapitulation of these findings in healthy volunteers suggests elements of consistent pharmacology compared to responses in mice although there are clear differences between these two systems.
DOI
10.1186/s13395-018-0179-5
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Billin, A. N., Honeycutt, S. E., McDougal, A. V., Kerr, J. P., Chen, Z., Freudenberg, J. M., ... & Fang, F. (2018). HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury. Skeletal muscle, 8(1), 35.
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