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ResearchIn-Press PreviewMetabolismMuscle biology Open Access | 10.1172/JCI195411

Distinct HIF1α and HIF2α functions control skeletal muscle metabolism and erythropoiesis

Junhyeong Lee,1 Merc Emil Matienzo,1 Sangyi Lim,1 Edzel Evallo,1 Yeongsin Kim,1 Sujin Jang,1 Keon Kim,1 Chang Hyeon Choi,1 Youn Ho Han,3 Chang-Min Lee,4 Tae-Il Jeon,5 Sang-Ik Park,4 Jun Wu,6 Dong-il Kim,7 and Min-Jung Park1

1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

Find articles by Kim, Y. in: PubMed | Google Scholar

1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

Find articles by Lee, C. in: PubMed | Google Scholar

1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

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1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

Find articles by Park, S. in: PubMed | Google Scholar

1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

Find articles by Wu, J. in: PubMed | Google Scholar

1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

Find articles by Kim, D. in: PubMed | Google Scholar

1Department of Veterinary Physiology, Chonnam National University, Gwangju, Korea, Republic of

2Department of Veterinary Physiology, Chonnam National University, Gwangju, Philippines

3Department of Oral Pharmacology, Wonkwang University, Korea, Republic of

4College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea, Republic of

5Department of Animal Science, Chonnam National University, Gwangju, Korea, Republic of

6Life Sciences Institute, University of Michigan, Ann Arbor, United States of America

7Department of Veterinary Physiology, Chonnam National Univeristy, Gwangju, Korea, Republic of

Find articles by Park, M. in: PubMed | Google Scholar

Published February 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI195411.
Copyright © 2026, Lee et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 17, 2026 - Version history
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Abstract

Skeletal muscle frequently experiences oxygen depletion, especially during exercise, and the alpha subunit of the hypoxia-inducible factors (HIF1α and HIF2α) plays a crucial role in mediating cellular adaptation to low oxygen levels. However, although significant, the absence of an appropriate experimental mouse model leaves the precise roles of HIFα in myofibers unclear. Therefore, this study developed mice with myofiber-specific knockouts of prolyl hydroxylase proteins (PHDs), in which HIFα is stabilized, and inducible myofiber-specific overexpression of stable HIF1α or HIF2α to explore the role of HIFα in myofibers. Using three distinct mouse models, we found that HIF1α increased the number of oxidative fibers but paradoxically impaired exercise performance and mitochondrial function. Comparatively, HIF2α exerted protection mechanisms against glucose intolerance and diet-induced obesity. Notably, HIF2α stabilization in skeletal muscle markedly elevated erythropoietin (EPO) levels in muscle and serum but not in the kidney and liver, suggesting skeletal muscle is a previously unrecognized site of EPO production in the body. Thus, this study demonstrates the distinct roles of HIF1α and HIF2α in skeletal muscle, newly uncovering that the PHD-HIF2α axis produces EPO from myofibers.

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  • Version 1 (February 17, 2026): In-Press Preview
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