Depp1 drives muscle loss under fasting and low oxygen in mice

In a new preprint, researchers studied mice to determine how low oxygen and nutrient scarcity trigger skeletal muscle loss. The authors found that hypoxia inducible factor (HIF) is necessary and sufficient to drive hypoxia-induced muscle atrophy. Using RNA sequencing of skeletal muscle from starved or hypoxic mice, they identified the gene Depp1. FoxO1 induced Depp1 expression during starvation, while HIF activation drove its expression during oxygen deprivation.

Whole-body deletion of Depp1 protected mice from muscle wasting during fasting and hypoxia. Conversely, overexpressing Depp1 directly caused skeletal muscle atrophy. Mechanistically, Depp1 localized to mitochondria and was required to activate autophagy and mitochondrial degradation in muscle tissue. The findings establish Depp1 as a shared atrogene acting downstream of both FoxO and HIF to trigger muscle breakdown.