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 Aug 15, 2026

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

Muscle cells rely on thousands of mitochondria, often described as the "powerhouse" of the cell, to generate energy. As mitochondria become damaged through normal use, cells remove and recycle them through a natural quality-control process called autophagy, a pathway that is also central to recycling other organelles and molecules. The focus of this project was to investigate autophagy in FSHD.

We first developed a new model by genetic engineering to monitor the progress of autophagy in unaffected and FSHD human muscle cells in real time using these fluorescent reporters. We discovered that muscle cells from people with FSHD have a previously unrecognised defect in activating autophagy when nutrients are scarce. Rather than mounting a normal protective response during periods of nutrient deprivation or fasting, FSHD muscle cells were unable to activate this recycling pathway efficiently, resulting in increased cellular stress and reduced survival. Importantly, autophagy could still be activated with drugs, indicating that it was only the sensing/induction phase that was defective.

Intermittent fasting has become increasingly popular because of its reported health benefits. However, our results suggest that prolonged fasting or nutrient deprivation may be detrimental for individuals with FSHD, as their muscle cells appear unable to activate some protective pathways required to cope with these conditions. Although further clinical studies are required, our findings indicate that dietary interventions involving fasting should be approached with caution in FSHD.

The project also identified another promising therapeutic opportunity. We found that Metformin, a widely prescribed and inexpensive medicine used to treat type 2 diabetes, significantly improved formation of muscle fibres in human FSHD muscle cells. Importantly, these laboratory findings translated into animal studies, where metformin improved muscle strength in a mouse model of FSHD. Our work suggests that metformin helps restore mitochondrial quality control, reducing accumulation of dysfunctional mitochondria and improving muscle health. Further clinical evaluation will be required before it can be recommended for use for FSHD, however the result is highly encouraging.

Overall, this project has provided important new insights into how defects in autophagy contribute to FSHD. We have also identified Metformin as a strong candidate for drug repurposing. The tools, datasets and discoveries generated through this Friends of FSH funded research form the foundation for a promising translational study that aims to bring effective treatments closer to people living with FSHD.