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Noninvasive ⁶⁴Cu-ATSM and PET/CT Assessment of Hypoxia in Rat Skeletal Muscles and Tendons During Muscle Contractions

¹ Institute of Sports Medicine, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; ² Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and ³ Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark

Correspondence: For correspondence or reprints contact: Dorthe Skovgaard, Institute of Sports Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, Copenhagen, Denmark, DK-2400. E-mail: dskovgaard{at}dadlnet.dk

The purpose of the present study was to investigate exercise-related changes in oxygenation in rat skeletal muscles and tendons noninvasively with PET/CT and the hypoxia-selective tracer ⁶⁴Cu-diacetyl bis(N⁴-methylthiosemicarbazone) (ATSM) and to quantitatively study concomitant changes in gene expression of 2 hypoxia-related genes, hypoxia-inducible factor 1 (HIF1) and carbonic anhydrase III (CAIII). Methods: Two groups of Wistar rats performed 1-leg contractions of the calf muscle by electrostimulation of the sciatic nerve. After 10 min of muscle contractions, ⁶⁴Cu-ATSM was injected and contractions were continued for 20 min. PET/CT of both hind limbs was performed immediately and 1 h after the contractions. The exercise group (n = 8) performed only muscle contractions as described, whereas the other group, exercise plus cuff (n = 8), in addition underwent cuff-induced hypoxia during the first PET/CT scan. Standardized uptake values (SUVs) were calculated for the Achilles tendons and triceps surae muscles and were correlated to gene expression of HIF1 and CAIII using real-time polymerase chain reaction. Results: Immediately after the contractions, uptake of ⁶⁴Cu-ATSM was significantly increased, by approximately 1.5-fold in muscles and 1.3-fold in tendons, compared with resting conditions. The significant increase was maintained in late PET scans in stimulated muscles and tendons independently of cuff application. In muscles, SUV correlated significantly with gene expression of HIF1 and CAIII, whereas this coherence was not found in tendons. Conclusion: We found enhanced uptake of ⁶⁴Cu-ATSM in both early and late PET scans, thereby supporting the possibility that ⁶⁴Cu-ATSM registers exercise-induced transient hypoxia in both skeletal muscles and force-transmitting tendons. The fact that skeletal muscles but not tendons showed upregulation of HIF1 and CAIII could indicate that healthy tendons are less responsive than skeletal muscles to low levels of oxygen.

Key Words: hypoxia • ⁶⁴Cu-ATSM • tendon • skeletal muscle • exercise

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