Fatty degeneration is observed in various neuromuscular diseases, but the mechanism(s) of its initiation remains unclear. To gain insight into the regulation of fatty degeneration, we employed a freeze-induced model of muscle degeneration/regeneration. Using this model, we examined the distribution of adipocyte-like cells with Oil Red-O staining and the expression pattern of adipogenic transcriptional factors, an adipocyte-terminal differentiation marker, and Wnt10b signaling molecules during muscle regeneration. Mice were subjected to freeze injury, and the gastrocnemius muscles were isolated 1, 3, 5, 7, 10, 14 and 28 days after surgery. Adipocyte-like cells with nuclei were readily observed, but not in normal muscle. Large amount of lipid accumulation was also observed in regenerating muscle. The area of Oil Red-O staining was significantly increased from 3 to 5 days after muscle injury and then rapidly decreased to almost control levels by day 10. Adipogenic transcriptional factors, sterol regulatory element binding protein-1c, CCAAT/enhancer-binding proteins α, β and δ, peroxisome-proliferator activated receptors γ1 and γ2, and the terminal differentiation marker, leptin were significantly up-regulated in the early stage of muscle regeneration, suggesting activation of the adipogenic potential. Secreted Frizzled-related protein-2, a Wnt pathway inhibitory protein, was strongly up-regulated 3 days after muscle injury, suggesting active repression of the Wnt10b pathway. In regenerating muscle, expression of CCAAT/enhancer-binding protein α and peroxisome-proliferator activated receptor γ2 proteins were increased 3 days after muscle injury. Taken together, our results suggest that adipogenic potential can be activated during muscle regeneration through increased adipogenic signaling in conjunction with decreased Wnt10b signaling.