Progress Update: Novel Therapeutics for FSHD: Mitochondria-targeted Antioxidants

Update by Dr. Heher
see grant Novel Therapeutics for FSHD: Mitochondria-targeted Antioxidants

It is well established that FSHD muscles are characterized by persistent metabolic disturbances. Oxidative stress and mitochondrial dysfunction have been identified as drivers of DUX4-induced muscle pathology, however, little is known about pathomechanisms leading to chronic metabolic stress in the disease. So far, antioxidant-based therapies aiming at ameliorating oxidative stress in FSHD patients have yielded only moderate functional muscle improvement in clinical trials. We believe that this rapidly translatable therapy could be improved if the mechanisms causing oxidative stress in FSHD were better understood. In this project, we thus aim to identify the biochemical origin of excess reactive oxygen species (ROS) observed in FSHD muscle cells, so we can find and test more targeted antioxidant-based therapies.

We have made good progress on this project so far, and found a pathomechanistic link between dysfunctional mitochondria, oxidative damage and impaired metabolic adaptation to low oxygen tension (hypoxia). We identified mitochondria as the major source of ROS in FSHD patient-derived and DUX4 expressing muscle cells, and further found that DUX4 expression in muscle cells induces mitochondrial dysfunction at a specific site in the mitochondrial respiratory chain. Excess mitochondrial ROS (mitoROS) cause oxidative damage within the mitochondria and dysfunctional FSHD mitochondria are characterized by impaired cellular oxygen consumption. As a consequence, FSHD muscle cells fail to adequately adapt their metabolism to conditions where oxygen availability is low (for example in working muscles during exercise), and are thus uniquely susceptible to hypoxic stress. Having identified mitochondria as the main source of ROS, we next examined whether specific targeting of mitoROS is a more potent therapeutic approach than use of conventional, non-targeted antioxidants: in vitro, mitochondria-targeted antioxidants were more capable of alleviating aspects of FSHD pathology compared to their non-targeted counterparts, especially under conditions of low oxygen tension. We are now studying the therapeutic potential of these mitochondria-targeted antioxidant compounds and their effects on metabolic adaptation in more detail, and will subsequently test the most potent compounds in a mouse model of FSHD.