ULK1 and ULK2: molecular modulators of autophagy and function in cardiac and skeletal muscles

Autophagy is a cellular process that acts as a recycling center for the cell by degrading long-lived proteins, protein aggregates, and cellular organelles. Impaired or insufficient autophagy has been implicated in aging, and in the progression of chronic disease states including those associated with neurodegeneration and obesity. In the heart, deficient autophagy is a feature of several cardiomyopathies leading to heart failure. In skeletal muscle, deficient autophagy is associated with skeletal muscle wasting and muscle weakness. However, the regulation of autophagy in cardiac and skeletal muscles remains poorly understood.

In these studies, we investigate the function of autophagy proteins ULK1 and ULK2 in cardiac and skeletal muscles. We show that loss of either ULK1 or ULK2 in the developing heart surprisingly enhances autophagy in adult mice while loss of both ULKs impairs autophagy and leads to age-associated heart failure. Interestingly, loss of ULK1 in the adult heart impairs autophagy and leads to rapid heart failure which is not prevented or delayed when autophagy is partially rescued indicating that ULK1 has autophagy independent functions in the heart critical to its function. Loss of ULK2 in the adult heart, however, has no discernible effect on autophagy or cardiac function. In skeletal muscle, loss of both ULK1 and ULK2 results in increased skeletal muscle size that is independent of autophagy, indicating that ULK1 and ULK2 have important autophagy-independent functions also in skeletal muscle. Together, our findings demonstrate that ULK1 and ULK2 regulate cardiac and skeletal muscle autophagy, as well as other important cellular processes, which are only beginning to be identified. These observations lay the foundation for future studies exploring ULK1 and ULK2 as therapeutic targets for cardiomyopathies and conditions where skeletal muscle atrophies.