Unraveling the role of the hypoxia factor HIF-2a in muscle atrophy.

Skeletal muscle is essential to life as it provides the mechanical power for locomotion and breathing. In our aging population, loss of muscle mass due to long- term inactivity is a major cause of morbidity and mortality. It is also a critical component of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), and although the role of muscle in ALS is debated improving muscle functioning prolongs survival. Thus, preventing muscle atrophy during inactivity is of major clinical importance.

Muscle mass is controlled by a balance between muscle protein synthesis and degradation. Signals controlling muscle growth or atrophy are distinct but finely interconnected. Besides cell intrinsic factors, oxygen levels may also control muscle mass. Indeed, in other tissues, the PHD/HIF oxygen sensing pathway controls cellular protein content, albeit in opposing manners. Studies from the Exercise Physiology lab of KU Leuven show that environmental hypoxia increases both skeletal muscle protein synthesis and breakdown, but it remains unclear whether HIFs are involved in muscle protein metabolism in vivo and control muscle mass during immobilization or denervation.

Interestingly, when measuring HIF-2α protein content in different models for muscle atrophy including hindlimb unloading, sciatic nerve dissection, and ALS, we found a consistent increase in HIF-2α protein content. This effect was restricted to conditions of ‘muscle inactivity’, as we could not detect muscular HIF-2α protein stabilization after exercise, which efficiently resulted in accumulation of HIF-1α. Also, hypoxia exposure did not affect HIF-2α, whereas it did increase HIF-1α protein content (5hr-11% O2). In addition, PHD1 knock-out mice, which have higher HIF-2α protein content, have lower muscle mass and higher FOXO3-levels, required for skeletal muscle atrophy.