Update: Exploring the interaction between mitochondrial dynamics and autophagy: can we counteract accumulation of dysfunctional mitochondria in FSHD muscle?

Posted by Friends of FSH Research on Jan 9, 2025

Report by Dr. Heher
See also Exploring the interaction between mitochondrial dynamics and autophagy: can we counteract accumulation of dysfunctional mitochondria in FSHD muscle?

The main aim of this research project is to examine the relationship between the batteries of a cell (mitochondria) and the main recycling pathway in a cell (autophagy) in FSHD. So far, we have examined what happens to mitochondria during the growth and formation of muscle fibres, which requires high amounts of energy and so more mitochondrial output, with accompanying changes to their number and structure. This process requires efficient autophagy, and we have found this to be perturbed in FSHD. Therefore, we have been testing drugs that target these processes to determine if they are beneficial for FSHD.

The drug Rapamycin is already used clinically for other conditions, and we observed a rapid remodelling of the mitochondria network in both unaffected and FSHD muscle cells. This indicates that the defective mitochondrial network can be remodelled in FSHD by enhancing autophagy. We also tested Metformin, which is the front-line drug for type 2 diabetes, and has shown some promise in the treatment of Duchenne Muscle Dystrophy. Some FSHD muscle cells responded positively and produced bigger muscle fibres with certain dosages of metformin. We are currently investigating these drugs further.

To examine autophagy directly, we have engineered muscle cells to display fluorescent markers that show how well autophagy is operating. Tracing the activity of autophagy in real-time shows that it is less effective in FSHD muscle cells. We are now using live imaging of these cells to track how autophagy responds to drugs. This information will further inform our understanding about the autophagy defect in FSHD.

Another aim of this project is to determine the link between the FSHD causative protein DUX4 and defects we observe in mitochondria and autophagy. We have muscle cells in which we can induce DUX4 while monitoring mitochondria. A mere 4h after DUX4 is induced, the mitochondrial network retracts and becomes knotted together (see image) and there is reduced autophagy. We are now investigating how DUX4 so quickly affects mitochondrial networks and autophagy.

Figure 1: Mitochondrial Network (Purple). Images of muscle cells (myoblast) stained for the mitochondrial network (Purple) showing the effect of the presence of DUX4 on the network. The induction of DUX4 (right) is indicated by staining the cells using an antibody which detects DUX4 in the nucleus of the cell (Green on the right). Scale bar is 15µm (0.015mm).