The aim of this study was to investigate the molecular mechanisms underlying heart and skeletal muscle damage in male Wistar rats weighing from 200 to 250 g at 180 mm Hg exposed to three hours of severe hypobaric hypoxia (5% O2) used as a model. Rats exposed to three hours of severe hypoxia presented a significant increase in plasma cardiac troponin I as compared to control, thus reflecting damage to the myocardium after exposure of rats to severe hypobaric hypoxia. At the same time, the administration of the HIF-1α transcription factor inhibitor into animals did not significantly affect plasma concentration of troponin I. On the contrary, in the case of the use of a none-specific myoglobin biomarker, there was no significant increase in its release into the blood after hypoxia compared with the control. At the same time, an experiment using topotecan as an inhibitor of HIF-1α showed that the amount of myoglobin in rat blood plasma one day after exposure of rats to severe hypobaric hypoxia was significantly less than in the absence of the inhibitor. Thus, it can be assumed that blocking the transcription factor HIF-1α for 10 minutes before exposure of animals to severe hypobaric hypoxia reduces damage to skeletal muscles. The mechanisms affecting the adaptation of heart and skeletal muscles to hypoxia are discussed.