Mitochondrial Complex I Deficiency Enhances Skeletal Myogenesis but Impairs Insulin Signaling through SIRT1 Inactivation

Jin Hong,Bong-Woo Kim,Hyo-Jung Choo,Jung-Jin Park,Jae-Sung Yi,Dong-Min Yu,Hyun Lee,Gye-Soon Yoon,Jae-Seon Lee,Young-Gyu Ko

doi:10.1074/jbc.m114.560078

Abstract

To address whether mitochondrial biogenesis is essential for skeletal myogenesis, C2C12 myogenesis was investigated after knockdown of NADH dehydrogenase (ubiquintone) flavoprotein 1 (NDUFV1), which is an oxidative phosphorylation complex I subunit that is the first subunit to accept electrons from NADH. The NDUFVI knockdown enhanced C2C12 myogenesis by decreasing the NAD(+)/NADH ratio and subsequently inactivating SIRT1 and SIRT1 activators (pyruvate, SRT1720, and resveratrol) abolished the NDUFV1 knockdown-induced myogenesis enhancement. However, the insulin-elicited activation of insulin receptor β (IRβ) and insulin receptor substrate-1 (IRS-1) was reduced with elevated levels of protein-tyrosine phosphatase 1B after NDUFV1 knockdown in C2C12 myotubes. The NDUFV1 knockdown-induced blockage of insulin signaling was released by protein-tyrosine phosphatase 1B knockdown in C2C12 myotubes, and we found that NDUFV1 or SIRT1 knockdown did not affect mitochondria biogenesis during C2C12 myogenesis. Based on these data, we can conclude that complex I dysfunction-induced SIRT1 inactivation leads to myogenesis enhancement but blocks insulin signaling without affecting mitochondria biogenesis.

Highlights

There is a big controversy about how mitochondria dysfunction affects skeletal myogenesis and insulin signaling
The NADH dehydrogenase (ubiquintone) flavoprotein 1 (NDUFV1) knockdown-induced blockage of insulin signaling was released by protein-tyrosine phosphatase 1B knockdown in C2C12 myotubes, and we found that NDUFV1 or Silent information regulator homologue 1 (SIRT1) knockdown did not affect mitochondria biogenesis during C2C12 myogenesis
CI Dysfunction Enhances Skeletal Myogenesis—The mitochondrial biogenesis that accompanies with skeletal myogenesis raises a big question as to whether increased mitochondrial function is essential for myogenesis [1]

Summary

Background

There is a big controversy about how mitochondria dysfunction affects skeletal myogenesis and insulin signaling. Results: Mitochondrial complex I deficiency inactivates SIRT1 by decreasing the NADϩ/NADH ratio, leading to skeletal myogenesis enhancement and insulin resistance. The NDUFV1 knockdown-induced blockage of insulin signaling was released by protein-tyrosine phosphatase 1B knockdown in C2C12 myotubes, and we found that NDUFV1 or SIRT1 knockdown did not affect mitochondria biogenesis during C2C12 myogenesis. PGC-1␣ in turn binds to and activates Mef to drive the formation of slow-oxidative muscle fibers that contain high numbers of mitochondria [4, 5] Through this positive auto-regulatory loop, skeletal myogenesis progresses with mitochondrial biogenesis [5]. Low glucose has been shown to prevent skeletal myogenesis by increasing the ratio of NADϩ to NADH and activating SIRT1, and low glucose-induced myogenesis inhibition is released by SIRT1 knockdown [38]. We demonstrate that SIRT1 is not required for mitochondrial biogenesis during skeletal myogenesis

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION