# Central role of AMPK in the regulation of skeletal muscle protein turnover

Anthony Sanchez, Alfredo Csibi, Audrey Raibon, Allan Pagano, Robin Candau, Henri Bernardi

► To cite this version:

Anthony Sanchez, Alfredo Csibi, Audrey Raibon, Allan Pagano, Robin Candau, et al. Central role of AMPK in the regulation of skeletal muscle protein turnover. 6. Colloque "Protéolyse Cellulaire" de la Société Française de Biochimie et Biologie Moléculaire (SFBBM), Nov 2012, Clermont-Ferrand, France. 2012. [hal-02746335](https://hal.inrae.fr/hal-02746335)

HAL Id: hal-02746335

https://hal.inrae.fr/hal-02746335

Submitted on 3 Jun 2020

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<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
## INTRODUCTION :

Skeletal muscle mass is depending upon a dynamic balance between anabolic and catabolic processes. At a cellular level, two major signaling pathways are involved: the transcription factors FoxO related pathway, implicated in the control of protein breakdown systems (ubiquitin-proteasome system and autophagy), and the IGF-1/Akt/mTORC1 pathway associated with the canonic pathway of protein synthesis and hypertrophy (3, 4). The aim of this study is to better understand the role played by the metabolic sensor system AMPK in the regulation of protein synthesis and breakdown. We show in muscle cells that the AMP-activated protein kinase (AMPK) decreases the mTORC1 pathway activity and simulates ubiquitin-proteasome and autophagy systems in a FoxO3-dependant manner. Furthermore, we identify Ulk1 as a new interacting partner of AMPK, which plays a major role in the autophagy induction.

## Regulation of muscular mass

### Signaling pathways:

<figure><img src="image_2.png" /></figure>

AMPK = metabolic sensor
activated by AICAR
Regulates FoxO3a (1, 4)

FoxO3a = transcription factor
of genes implicated in autophagy(2)

<figure><img src="image_3.png" /></figure>

## AICAR induces autophagy in proliferating C2C12 cells and primary myotubes

<figure><img src="image_4.png" /><figcaption>Primary myotubes, differentiation (D4)</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>AMPK activation increases autophagic fluxes in primary myotubes</figcaption></figure>

## AICAR inhibits protein translation and induces protein ubiquitination

<figure><img src="image_6.png" /><figcaption>Primary myotubes, differentiation (D4)</figcaption></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

## FoxO3a-dépendent regulation of autophagy induced by AMPK activation

<figure><img src="image_11.png" /><figcaption>Primary myotubes, differentiation (D4)</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>AMPK interacts with FoxO3a and induces Ser-588 phosphorylation</figcaption></figure>

<figure><img src="image_13.png" /></figure>

A
consensus
Ulk1
Ser467
FoxO3a
Ser588
Q
S
T
A
R
L
S

B
control
AICAR

A
control
AICAR

<figure><img src="image_14.png" /><figcaption>AMPK stabilizes FoxO3a</figcaption></figure>

<figure><img src="image_15.png" /></figure>

## Ulk1 : A new target of AMPK

<figure><img src="image_16.png" /><figcaption>Proliferating myoblasts</figcaption></figure>

Ser467/
FoxO3A
Ser588
Q
T
L
S

<figure><img src="image_17.png" /></figure>

Control
AICAR
150 kDa
Ulk1
Phospho Ser467

<figure><img src="image_18.png" /><figcaption>Dynamique du complexe ???</figcaption></figure>

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /></figure>

## CONCLUSION :

In this study, we identified AMPK-associated signaling pathways implicated in the muscular mass regulation. The

characterization of a new interacting partner of AMPK, essential to the autophagy process suggests novel therapeutic

perspectives in the treatment of myopathies associated to an increase of proteolysis.

## REFERENCES :

(1) Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A. (2007). *J Biol Chem*, 282(41):30107-19.

(2) Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007). *Cell Metab.* 6(6):458-71.

(3) Rivas DA, Lessard SJ, Coffey VG (2009). *Appl Physiol Nutr Metab*, 34(5):807-16, pour revue.

(4) Sanchez AMJ, Candau RB, Csibi A, Pagano AF, Raibon A, Bernardi H. (2012). *Am J Physiol Cell Physiol*, 303(5):C475-85 for review.

## Conservation des résultats In vivo ???

<figure><img src="image_22.png" /><figcaption>Formation de vésicules autophagiques dans les fibres électroporées avec des formes activées de l'AMPK ou de FoxO3a</figcaption></figure>

## In summary

<figure><img src="image_23.png" /></figure>