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Research Article

FOXO Signaling is Required for Disuse Muscle Atrophy and is Directly Regulated by Hsp70

¹University of Florida

Submitted 17 July 2009 ; revised 2 October 2009 ; accepted in final form 25 October 2009

The purpose of the current study was to determine if Heat shock protein 70 (Hsp70) directly regulates Forkhead Box O (FOXO) signaling in skeletal muscle. This aim stems from previous work demonstrating that Hsp70 overexpression inhibits disuse-induced FOXO transactivation and prevents muscle fiber atrophy. However, although FOXO is sufficient to cause muscle wasting, no data currently exist on the requirement of FOXO signaling in the progression of physiological muscle wasting, in vivo. In the current study we show that specific inhibition of FOXO, via expression of a dominant negative FOXO3a, in rat soleus muscle during disuse prevented >40% of muscle fiber atrophy, demonstrating FOXO signaling is required for disuse muscle atrophy. Subsequent experiments determined if Hsp70 directly regulates FOXO3a signaling when independently activated in skeletal muscle, via transfection of FOXO3a. We show that Hsp70 inhibits FOXO3a-dependent transcription in a gene-specific manner. Specifically, Hsp70 inhibited FOXO3a-induced promoter activation of atrogin-1, but not MuRF1. Further studies showed that a FOXO3a DNA-binding mutant can activate MuRF1, but not atrogin-1, suggesting FOXO3a activates these two genes through differential mechanisms. In summary, FOXO3a signaling is required for physiological muscle atrophy and is directly inhibited by Hsp70.

atrogin-1; MAFbx; MuRF1; transcriptional regulation; DNA binding