Transcriptional Changes Involved in Atrophying Muscles during Prolonged Fasting in Rats

Food deprivation resulting in muscle atrophy may be detrimental to health. To better understand how muscle mass is regulated during such a nutritional challenge, the current study deciphered muscle responses during phase 2 (P2, protein sparing) and phase 3 (P3, protein mobilization) of prolonged fasting in rats. This was done using transcriptomics analysis and a series of biochemistry measurements. The main findings highlight changes for plasma catabolic and anabolic stimuli, as well as for muscle transcriptome, energy metabolism, and oxidative stress. Changes were generally consistent with the intense use of lipids as fuels during P2. They also reflected increased muscle protein degradation and repressed synthesis, in a more marked manner during P3 than P2 compared to the fed state. Nevertheless, several unexpected changes appeared to be in favor of muscle protein synthesis during fasting, notably at the level of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, transcription and translation processes, and the response to oxidative stress. Such mechanisms might promote protein sparing during P2 and prepare the restoration of the protein compartment during P3 in anticipation of food intake for optimizing the effects of an upcoming refeeding, thereby promoting body maintenance and survival. Future studies should examine relevance of such targets for improving nitrogen balance during catabolic diseases.