Pulmonary surfactant protein A (Surfactant protein A, SP-A) is the most abundant pulmonary surfactant protein, encoded and synthesized by the SFTPA gene. SP-A is primarily synthesized in the lung tissue of mammals and is also expressed in tissues such as skeletal muscle. SP-A has functions including reducing pulmonary surface tension, enhancing pulmonary gas exchange, regulating immunity, clearing pathogens, and reducing inflammatory responses. In this study, after performing transcriptome sequencing analysis on the liver, lung, skeletal muscle, small intestine, colon, and adipose tissues from SD rats (2 250 m and 3 700 m) and plateau zokors (2 700 m and 3 700 m) at different altitudes; the expression levels of SFTPA gene in skeletal muscle and lung tissues of the two species were compared and analyzed by qRT-PCR; the expression levels of SP-A in skeletal muscle, lung tissue and serum of the two species were compared and analyzed by Western Blotting. The transcriptome analysis revealed that with increasing altitude, the expression of the SFTPA gene in the skeletal muscle of SD rats were significantly up-regulated, while in the skeletal muscle of plateau zokors, there were no significant difference in its expression; the qRT-PCR results showed that with increasing altitude and decreasing environmental oxygen levels, the expression of SFTPA in the skeletal muscle of SD rats increased, whereas in the skeletal muscle of plateau zokors, the expression of SFTPA significantly decreased. Furthermore, the expression of SFTPA in the lung tissues of both SD rats and plateau zokors were significantly decreased; the Western Blotting results showed that with increasing altitude and decreasing environmental oxygen levels, the expression levels of SP-A in the skeletal muscle, serum, and lung tissues of both SD rats and plateau zokors were significantly increased. In conclusion, in a high-altitude hypoxia environment, the transcriptional expression of the SFTPA gene in the lung tissues of SD rats and plateau zokors were significantly decreased. However, the content of SP-A in their lung tissues not only did not decrease but significantly increased. This may be due to SP-A synthesized and secreted by skeletal muscle being transported to the lung tissues via the bloodstream, representing an important mechanism for SD rats and plateau zokors to adapt to hypoxia environments.