Year: 2026
Type: preprint
Abstract: Nutrients and oxygen are sensed within the muscle to control growth and disruption of either signal is sufficient to lead to muscle atrophy 1 . While nutrient limitation is sensed via a conserved transcriptional atrophy program (commonly referred to as “atrogenes”) dictated via the Forkhead box O (FoxO) transcription factors, how low oxygen promotes muscle loss remains unknown 2 . Accordingly, the downstream mechanisms that initiate muscle loss when oxygen and nutrients are limiting are only partly understood 3 . Here, we find Hypoxia Inducible Factor (HIF), the master regulator of our adaptation to low oxygen, is necessary and sufficient to mediate muscle loss under hypoxia in mice. RNA sequencing in skeletal muscle isolated from starved or hypoxic mice identifies Decidual Protein Induced by Progesterone 1 (Depp1), which is induced in skeletal muscle when nutrients or oxygen is limiting via FoxO1 and HIF activation, respectively. Whole body Depp1 loss in mice reduces muscle loss under fasting and hypoxia and skeletal muscle Depp1 overexpression is sufficient to mediate muscle atrophy. Mechanistically, Depp1 localizes to the mitochondria and is necessary to control autophagy activation and mitochondrial degradation in skeletal muscle. Taken together, our studies nominate Depp1 as a new “atrogene” necessary for muscle loss under multiple atrophy scenarios involving FoxO and HIF. Significance Nutrients or oxygen are necessary to maintain muscle mass and when lost lead to muscle atrophy. While nutrient limitation has been shown to lead to muscle loss via the FoxO family of transcription factors, how we lose muscle mass when oxygen is limiting remains unknown. Here, we identify an overlapping atrophy mechanism that converges on Depp1, which is induced in skeletal muscle when nutrients or oxygen is limiting via the FoxO and Hypoxia Inducible Factor transcription factors. Mechanistically, Depp1 is necessary and sufficient to mediate muscle loss and is critical to maintain mitochondrial abundance under these conditions. These findings have the potential to inform how to preserve muscle mass under diverse pathophysiological scenarios where nutrients or oxygen are limiting.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Massachusetts General Hospital
OpenAlex ID: W7214628013