Adss1, encoding adenylosuccinate synthetase 1, is a key enzyme in adenine nucleotide biosynthesis [2]. It is a component of the purine nucleotide cycle, a muscle-specific metabolic cycle [3]. The gene is predominantly expressed in striated muscle tissues, and its expression pattern is developmentally regulated [1,3]. Genetic models, like mouse models, can be valuable for studying its functions.

In rodent models of surgically induced cardiac hypertrophy, Adss1 is up-regulated [2]. In vitro, in rat neonatal cardiomyocytes treated with angiotensin II, a signaling cascade activates the Adss1 gene, and this induction is blocked by cyclosporin A, suggesting calcineurin involvement [2]. In an in vitro model of cardiac hypertrophy (electrically stimulated pacing of cultured cardiomyocytes), Adss1 activation involves the calcineurin-mediated dephosphorylation of NFAT3 and increased synthesis of GATA4 [5]. ADSS1 myopathy, an autosomal recessive muscle disease caused by variants in Adss1, is associated with respiratory muscle weakness, cardiomyopathy, and limb muscle weakness [4]. Loss of Adss1 is also observed in lung adenocarcinoma, both in mouse and human cell lines, suggesting its role in lung carcinogenesis [6].

In conclusion, Adss1 is crucial for adenine nucleotide biosynthesis, especially in muscle tissues. Its up-regulation in cardiac hypertrophy and its role in ADSS1 myopathy and lung adenocarcinoma, as revealed through in vivo and in vitro models, highlight its significance in muscle-related and cancer-related biological processes. These findings from model-based research contribute to understanding the underlying mechanisms of these diseases and potentially developing targeted therapies.

References:

1. Li, Xinyun, Zhu, Zhengmao, Mo, Delin, Zhao, Shuhong, Li, Kui. 2007. Comparative molecular characterization of ADSS1 and ADSS2 genes in pig (Sus scrofa). In Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology, 147, 271-7. doi:. https://pubmed.ncbi.nlm.nih.gov/17347008/

2. Wen, H Y, Xia, Y, Young, M E, Taegtmeyer, H, Kellems, R E. . The adenylosuccinate synthetase-1 gene is activated in the hypertrophied heart. In Journal of cellular and molecular medicine, 6, 235-43. doi:. https://pubmed.ncbi.nlm.nih.gov/12169208/

3. Lewis, A L, Guicherit, O M, Datta, S K, Hanten, G R, Kellems, R E. . Structure and expression of the murine muscle adenylosuccinate synthetase gene. In The Journal of biological chemistry, 271, 22647-56. doi:. https://pubmed.ncbi.nlm.nih.gov/8798436/

4. Hama, Yuka, Sano, Terunori, Oya, Yasushi, Takahashi, Yuji, Takao, Masaki. 2025. Two Brothers With ADSS1 Myopathy: A Report of Clinical, Radiological, and Autopsy Findings. In Neuropathology : official journal of the Japanese Society of Neuropathology, , . doi:10.1111/neup.70008. https://pubmed.ncbi.nlm.nih.gov/40302423/

5. Xia, Y, McMillin, J B, Lewis, A, Williams, R S, Kellems, R E. . Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene. In The Journal of biological chemistry, 275, 1855-63. doi:. https://pubmed.ncbi.nlm.nih.gov/10636885/

6. Miller, Joshua C, Blake, Daniel C, Herzog, Christopher R. . Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma. In Molecular carcinogenesis, 48, 1116-22. doi:10.1002/mc.20563. https://pubmed.ncbi.nlm.nih.gov/19603421/