HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury
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 tra...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-11-01
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| Series: | Skeletal Muscle |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13395-018-0179-5 |
| _version_ | 1818013950769364992 |
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| author | Andrew N. Billin Samuel E. Honeycutt Alan V. McDougal Jaclyn P. Kerr Zhe Chen Johannes M. Freudenberg Deepak K. Rajpal Guizhen Luo Henning Fritz Kramer Robert S. Geske Frank Fang Bert Yao Richard V. Clark John Lepore Alex Cobitz Ram Miller Kazunori Nosaka Aaron C. Hinken Alan J. Russell |
| author_facet | Andrew N. Billin Samuel E. Honeycutt Alan V. McDougal Jaclyn P. Kerr Zhe Chen Johannes M. Freudenberg Deepak K. Rajpal Guizhen Luo Henning Fritz Kramer Robert S. Geske Frank Fang Bert Yao Richard V. Clark John Lepore Alex Cobitz Ram Miller Kazunori Nosaka Aaron C. Hinken Alan J. Russell |
| author_sort | Andrew N. Billin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T06:39:37Z |
| format | Article |
| id | doaj.art-e1f73e6f4eda4a62a3d79d3777de791e |
| institution | Directory Open Access Journal |
| issn | 2044-5040 |
| language | English |
| last_indexed | 2024-04-14T06:39:37Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Skeletal Muscle |
| spelling | doaj.art-e1f73e6f4eda4a62a3d79d3777de791e2022-12-22T02:07:22ZengBMCSkeletal Muscle2044-50402018-11-018111410.1186/s13395-018-0179-5HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injuryAndrew N. Billin0Samuel E. Honeycutt1Alan V. McDougal2Jaclyn P. Kerr3Zhe Chen4Johannes M. Freudenberg5Deepak K. Rajpal6Guizhen Luo7Henning Fritz Kramer8Robert S. Geske9Frank Fang10Bert Yao11Richard V. Clark12John Lepore13Alex Cobitz14Ram Miller15Kazunori Nosaka16Aaron C. Hinken17Alan J. Russell18Muscle Metabolism Discovery Performance Unit, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineTarget Sciences, GlaxoSmithKlineTarget Sciences, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineTarget Sciences, GlaxoSmithKlineClinical Statistics, GlaxoSmithKlineMetabolic Pathways and Cardiovascular Therapy Area, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineMetabolic Pathways and Cardiovascular Therapy Area, GlaxoSmithKlineMetabolic Pathways and Cardiovascular Therapy Area, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineSchool of Medical and Health Sciences, Edith Cowan UniversityMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineMuscle Metabolism Discovery Performance Unit, GlaxoSmithKlineAbstract 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.http://link.springer.com/article/10.1186/s13395-018-0179-5Eccentric injuryHIF activationSkeletal muscleProlyl hydroxylaseProtection |
| spellingShingle | Andrew N. Billin Samuel E. Honeycutt Alan V. McDougal Jaclyn P. Kerr Zhe Chen Johannes M. Freudenberg Deepak K. Rajpal Guizhen Luo Henning Fritz Kramer Robert S. Geske Frank Fang Bert Yao Richard V. Clark John Lepore Alex Cobitz Ram Miller Kazunori Nosaka Aaron C. Hinken Alan J. Russell HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury Skeletal Muscle Eccentric injury HIF activation Skeletal muscle Prolyl hydroxylase Protection |
| title | HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury |
| title_full | HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury |
| title_fullStr | HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury |
| title_full_unstemmed | HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury |
| title_short | HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury |
| title_sort | hif prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction induced injury |
| topic | Eccentric injury HIF activation Skeletal muscle Prolyl hydroxylase Protection |
| url | http://link.springer.com/article/10.1186/s13395-018-0179-5 |
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