Regulation of the Intracellular Localization of Foxo3a by Stress-Activated Protein Kinase Signaling Pathways in Skeletal Muscle Cells

Abstract

Muscle atrophy is a debilitating process associated with many chronic wasting diseases, like cancer, diabetes, sepsis, and renal failure. Rapid loss of muscle mass occurs mainly through the activation of protein breakdown by the ubiquitin proteasome pathway. Foxo3a transcription factor is critical for muscle atrophy, since it activates the expression of ubiquitin ligase Atrogin-1. In several models of atrophy, inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway induces nuclear import of Foxo3a through an Akt-dependent process. This study aimed to identify signaling pathways involved in the control of Foxo3a nuclear translocation in muscle cells. We observed that after nuclear import of Foxo3a by PI3K/Akt pathway inhibition, activation of stress-activated protein kinase (SAPK) pathways induced nuclear export of Foxo3a through CRM1. This mechanism involved the c-Jun NH₂-terminal kinase (JNK) signaling pathway and was independent of Akt. Likewise, we showed that inhibition of p38 induced a massive nuclear relocalization of Foxo3a. Our results thus suggest that SAPKs are involved in the control of Foxo3a nucleocytoplasmic translocation in C2C12 cells. Moreover, activation of SAPKs decreases the expression of Atrogin-1, and stable C2C12 myotubes, in which the p38 pathway is constitutively activated, present partial protection against atrophy.

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This work was supported by the National Research Agency (Project Lip-Age, no. ANR-07-PNRA-021) and the French Association against Myopathies (grant no. 6073).

We thank B. Mograbi (EA 4319/INSERM ERI-21, Nice, France) for kindly providing us some Akt mutants, M. Deckert (U576, l'Archet Hospital, Nice, France) for the Foxo3a-GFP and FHRE-Luc plasmids, and P. Martin and P. Pognonec for retroviral constructs (FRE 3094, Faculty of Sciences, Nice, France). We are also grateful to B. Voiland, C. Mondini, and F. Courtin for their technical assistance and to E. Kurkdjian for her engineering expertise and support.