Tissue-Specific Splicing and Dietary Interaction of a Mutant As160 Allele Determine Muscle Metabolic Fitness in Rodents

• Main Authors: Xinyu Yang (197010), Qiaoli Chen (538344), Qian Ouyang (693521), Ping Rong (10756155), Weikuan Feng (10756158), Chao Quan (449518), Min Li (12799), Qing Jiang (197843), Hui Liang (503201), Tong-Jin Zhao (10756164), Hong Yu Wang (10756167), Shuai Chen (506142)
• Format: Still Image
• Language: unknown
• Published: 2021
• Subjects: Biological Sciences not elsewhere classified; AS160; mutation; splicing; insulin resistance; glucose uptake; lipid metabolism; skeletal muscle; inuit
• Online Access: https://doi.org/10.2337/figshare.14547156.v1

Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160 R684X mutation that causes type 2 diabetes. Whether this mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically-modified rat model bearing an orthologous AS160 R693X mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160 R693X rats. The AS160 R693X mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilisation but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilisation in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160 R684X mutation.