Enrichment of habitat of the captive rodents Heterocephalus glaber (naked mole rats) allowing them to implement the innate behavioral pattern of digging through hard soil somehow led to the emergence of unusual animals showing signs of cachexia in the colony; these differed from other animals by the reduced body mass index associated with subcutaneous fat reduction. Furthermore, the animals itself showed aggressive eating behavior, but showed no weight gain even after stopping digging due to detachment of the camera with soil. The study aimed to clarify the pathogenetic mechanism underlying the reported phenomenon. For that animals showing signs of cachexia (one female and two males aged 4–5 years) were withdrawn from the colony, along with the animals showing no such signs (two females and one male aged 4–5 years) as controls. Histologic assessment of tissues revealed cardiac hypertrophy and hyperlipofuscinosis of the liver. Cardiac hypertrophy was also suggested by the results of the animal heart microRNA sequencing bioinformatics analysis that revealed elevated levels of microRNA responsible for the increased cell division activity and reduced apoptotic activity in the heart. These data suggest that the animals living in the habitat with the increased oxygen content (21% vs. 8% in the natural habitat, underground) experienced severe oxidative stress during physical activity, which resulted in dysfunction of body’s regulatory systems, increased metabolism at rest, cardiovascular system overload, and damage to organs and tissues. Thus, naked mole rats can have normal physical activity only under conditions of low oxygen content.