Enhanced mitochondria - sarco-endoplasmic reticulum association in skeletal muscle insulin resistance is mediated by PDK4
Themis Thoudam1, 2, Dipanjan Chanda4, Ji-Min Lee1, 2, Byong-Keol Min1, 2, Hoyul Lee4, Bo-Yoon Park1,2, Sinam Ibotombi Singh1,2, Hyeon-Ji Kang4, Sungmi Park4, Won-il Choi4, Jae-Han Jeon3, Keun-Gyu Park3, , In-Kyu Lee1, 2, 3,4
1Department of Biomedical Science, Graduate School, 2BK21 Plus KNU Biomedical Convergence Program, 3Department of Internal Medicine, Kyungpook National University;
4Leading-edge Research Center for Drug Discovery and Development, Kyungpook National University Hospital, Kyungpook National University Medical Center, Daegu, Republic of Korea
IP3R1, GRP75 and VDAC1 protein complex regulates calcium transfer from ER to mitochondria via formation of mitochondria associated ER membrane (MAM). MAM has been depicted to be a mediator of insulin resistance in hepatic tissue but its role in skeletal muscle tissue remain undetermined. Additionally, pyruvate dehydrogenase kinase 4 (PDK4), which regulates the conversion of pyruvate to acetyl CoA by inactivating pyruvate dehydrogenase complex, is highly upregulated in skeletal muscle tissue of obese and diabetic subjects. Interestingly, we found that PDK4 is abundantly expressed in MAM and it physically interacts with IP3R1, GRP75 and VDAC1 complex at the MAM interface. In this study, we investigated the role of PDK4 in MAM formation and its contribution in development of insulin resistance in skeletal muscle. Suppression of PDK4 gene expression or its kinase activity hindered IP3R1, GRP75 and VDAC1 complex formation. Saturated fatty acid (FA) treatment and high fat diet upregulated PDK4 protein level which was accompanied by increased MAM formation in skeletal muscle. Conversely, suppression of IP3R1, GRP75 or PDK4 expression protected from FA-induced mitochondrial dysfunction and ER stress in skeletal muscle. Furthermore, suppression of MAM formation attenuated c-Jun N-Terminal kinase (JNK) mediated inhibition of insulin signaling pathway and improved insulin sensitivity in skeletal muscle. In conclusion, our study demonstrates a novel mediatory role of PDK4 in the context of mitochondrial dysfunction and insulin resistance in skeletal muscle.