Targeting ALDH2 to promote skeletal muscle health: A novel strategy against mitochondrial dysfunction

The maintenance of skeletal muscle relies on several cellular signalling pathways directly linked to mitochondrial function. Mitochondria support skeletal muscle bioenergetics and are known as a primary source of reactive oxygen species (ROS). Indeed, mitochondrial dysfunction-induced excessive ROS accumulation leads to irreversible molecular damage caused by lipid peroxidation by product 4-hydroxy-trans-2-nonenal (4-HNE), this is able to directly inactivate proteins and DNA, causing mitochondrial and cellular dysfunction. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme responsible for counteracting this deleterious cycle by detoxifying aldehydes and converting them into less harmful molecules. In this context, ALDH2 is essential for functional skeletal muscle maintenance. In fact, studies published in the last decade show that ALDH2 overexpression downregulates atrophic genes; meanwhile, the lack of this protein is associated with muscle weakness and atrophy, demonstrating its relevance for maintaining muscle mass. In this context, interventions capable of increasing ALDH2 levels and/or activity are considered promising therapeutic strategies for mitigating oxidative damage, enhancing mitochondrial function, and preserving muscle integrity under adverse conditions.