Down-regulation of the mitochondrial i-AAA protease Yme1L induces muscle atrophy via FoxO3a and myostatin activation.

Yoo Jeong Lee,Gyu Hee Kim,Sang Ick Park,Joo Hyun Lim

doi:10.1111/jcmm.14799

Yoo Jeong Lee, Gyu Hee Kim + Show 2 more

Open Access

https://doi.org/10.1111/jcmm.14799

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Abstract

Muscle atrophy is closely associated with many diseases, including diabetes and cardiac failure. Growing evidence has shown that mitochondrial dysfunction is related to muscle atrophy; however, the underlying mechanisms are still unclear. To elucidate how mitochondrial dysfunction causes muscle atrophy, we used hindlimb‐immobilized mice. Mitochondrial function is optimized by balancing mitochondrial dynamics, and we observed that this balance shifted towards mitochondrial fission and that MuRF1 and atrogin‐1 expression levels were elevated in these mice. We also found that the expression of yeast mitochondrial escape 1‐like ATPase (Yme1L), a mitochondrial AAA protease was significantly reduced both in hindlimb‐immobilized mice and carbonyl cyanide m‐chlorophenylhydrazone (CCCP)‐treated C2C12 myotubes. When Yme1L was depleted in myotubes, the short form of optic atrophy 1 (Opa1) accumulated, leading to mitochondrial fragmentation. Moreover, a loss of Yme1L, but not of LonP1, activated AMPK and FoxO3a and concomitantly increased MuRF1 in C2C12 myotubes. Intriguingly, the expression of myostatin, a myokine responsible for muscle protein degradation, was significantly increased by the transient knock‐down of Yme1L. Taken together, our results suggest that a deficiency in Yme1L and the consequential imbalance in mitochondrial dynamics result in the activation of FoxO3a and myostatin, which contribute to the pathological state of muscle atrophy.

Highlights

Muscle atrophy is considered to be closely associated with many diseases, including cardiac failure and diabetes 1; the underlying mechanisms still unclear
We demonstrated that muscle atrophy was closely related to an imbalance in the mitochondrial quality control system
We showed that the loss of yeast mitochondrial escape 1‐like ATPase (Yme1L) results in muscle atrophy via the elevation of Oma[1] and the concomitant ac‐ cumulation of the short form of Opa[1]; the depletion of LonP1 in C2C12 myotubes did not directly induce muscle atrophy (Figure 5E)

Summary

| INTRODUCTION

Muscle atrophy is considered to be closely associated with many diseases, including cardiac failure and diabetes 1; the underlying mechanisms still unclear. Opa[1] has various isoforms, eight in humans and four in mice, and the long form (L‐Opa1) and short form (S‐Opa1) of Opa[1] are generated by alternative splicing or proteolytic cleavage Under normal conditions, these forms exist at almost equimolar concentrations, and the loss of L‐Opa[1] leads to mitochondrial fragmentation.[8] Mitochondrial fission requires the re‐ cruitment of dynamin‐related protein 1 (Drp1), another type of dy‐ namin‐related GTPase, to the OMM and the formation of multiple ring complexes. A deficiency in Yme1L accelerated this imbalance to‐ wards mitochondrial fission and mitophagy, subsequently activating FoxO3a and myostatin, which are essential for the degradation of muscle proteins. Yme1L plays an important role in the maintaining healthy mitochondria in the muscle and loss of Yme[1] induces the pathological state of muscle atrophy

| MATERIALS AND METHODS

Findings

| DISCUSSION