Skeletal muscles—responsible for movement, joint stabilization, and postural support—are highly metabolically active and heavily reliant on oxygen during physical activity. However, conditions such as high-intensity exercise or sustained exertion frequently expose skeletal muscles to reduced oxygen availability, which can compromise muscle homeostasis.
Cells respond to this stress through hypoxia-inducible factor alpha (HIFα), a key transcription factor family induced by oxygen deficiency. The two major isoforms, HIF1α and HIF2α, regulate both shared and distinct target genes involved in glucose metabolism, mitochondrial function, angiogenesis, and erythropoiesis. Despite their established roles, the specific functions of HIF1α and HIF2α within myofibers remain poorly understood, largely due to the absence of appropriate in vivo models.
To untangle these roles, a research team led by Professor Dong-il Kim and Professor Min-Jung Park generated myofiber-specific mouse models with either all three prolyl hydroxylase domains (PHDs) removed—which normally keep HIF activity in check—or with HIF1α or HIF2α selectively stabilized in skeletal muscle. This paper was made available online on February 17, 2026, and was published in Volume 136 Issue 8 of the Journal of Clinical Investigation on April 15, 2026. This design allowed the researchers to compare the two HIF pathways directly rather than treating muscle oxygen sensing as a single switch.
The findings were striking. Despite both being oxygen-sensitive transcription factors, HIF1α and HIF2α regulate distinct aspects of muscle physiology and systemic metabolism. HIF1α stabilization increased the proportion of oxidative muscle fibers, a feature often associated with endurance. Yet the mice performed worse on treadmill tests and showed impaired mitochondrial oxidative phosphorylation. The muscle looked more endurance-like on the surface, but its underlying energy machinery was compromised. "This study demonstrates the distinct, non-redundant roles of HIF1α and HIF2α in skeletal muscle, highlighting that selectively targeting each isoform can lead to very different physiological outcomes," Prof. Park explains.
HIF2α showed contrasting effects. Its activation in mice improved glucose tolerance, reduced weight gain, preserved mitochondrial function, and was associated with lower food intake and higher GLP-1 levels. Most unexpectedly, HIF2α also drove skeletal muscle to produce and secrete erythropoietin (EPO)—a hormone conventionally attributed to the kidneys and liver. When the researchers selectively deleted EPO from muscle, the hematological abnormalities seen in PHD triple-knockout mice normalized, confirming that the PHD–HIF2α axis produces EPO from myofibers. "This indicates that skeletal muscle may represent an additional source of EPO production and erythropoiesis when HIF2α is activated. Given the medical importance of EPO biology, this may be one of the most novel and exciting findings of our study," notes Prof. Kim.
The findings carry broad implications for metabolic disease, exercise physiology, and anemia research. By showing that skeletal muscle can influence whole-body glucose handling and red blood cell production through distinct HIF pathways, the study reinforces a growing view of muscle as an endocrine organ, not merely a tissue for movement. The authors caution that the work was performed in mouse models, and further studies are needed before any clinical application can be considered. The study also raises important safety questions. Because pharmacological PHD inhibitors stabilize HIF pathways and are used or investigated for anemia, the authors note that systemic manipulation of these pathways should be considered carefully, especially given the potential for muscle dysfunction or excessive red blood cell production. "HIF2α-driven EPO production does not appear to occur in skeletal muscle under normal conditions, but muscle-derived EPO may become relevant when kidney EPO production is impaired," Park added.
In the longer term, understanding how HIF1α and HIF2α act differently in muscle may help guide more precise, isoform-specific strategies for metabolic disorders, age-related muscle decline, exercise intolerance, and diseases involving impaired oxygen delivery.
