Silvia Di Francescantonio is a postdoctoral researcher at the Gulbenkian Institute for Molecular Medicine. There, she studies skeletal muscle mechanics and tissue health. In this Postdoc Portrait interview, she shares her passion for working with skeletal muscle and the challenges these myofibers present to researchers.
Unraveling Skeletal Muscle Biology Development and Homeostasis
Q | What drew you to skeletal muscle biology?
I have been working on skeletal muscle biology since before my PhD, although it was not where I expected my research career to end up. During my master's studies, I was convinced that I would dedicate my career to malaria research. I imagined traveling the world and working on a disease that affects millions of people. Instead, I ended up joining a project on epigenetics in skeletal muscle and it was genuinely love at first sight.
I was fascinated by skeletal muscle. It is a beautiful tissue to study, allowing researchers to combine everything from microscopy and cell biology to physiology and animal studies. I was impressed by its remarkable ability to regenerate, which opens exciting possibilities for regenerative medicine.
The more I learned, the more I realized how much remains to be discovered. Many skeletal muscle disorders still have no cure and answering big questions in the field requires bringing together knowledge from genomics, metabolism, tissue regeneration, and biomechanics. There is always something new to learn.
And finally, did you know that a single skeletal muscle fiber in the human leg can be nearly 40 centimeters long? How cool is that?
Q | What scientific problem are you trying to solve?
As a cell biologist, I spent my postdoctoral years studying skeletal muscle cells, or myofibers, to understand how they develop, mature, and maintain healthy function throughout life. One question that particularly interested us was how the actin-based cellular machinery that enables cells to move and change shape contributes to the formation of these cells during development.
As tissue biologist and physiology-lover, I have also investigated how defects in this actin-dependent cellular machinery affect muscle structure and function in vivo. Using animal models and behavioral studies, I aim to understand how disruptions at the cellular level can lead to changes in muscle performance and overall tissue health.
More recently, I have become interested in how skeletal muscle cells withstand the repeated mechanical forces generated during contraction. In particular, we are investigating the cellular signaling pathways that help cell nuclei resist mechanical stress and maintain their integrity despite the constant demands placed on muscle tissue. Understanding these protective mechanisms could explain how muscles remain healthy and functional throughout life.
Overcoming Technical Challenges in Muscle Physiology
Q | What’s one thing you learned from your research that you didn’t expect?
One general thing I learned is that the most difficult scientific questions are often the ones most worth pursuing. Early in my career, I sometimes saw technical challenges as barriers. Now, I see them as clues that there is something important left to discover.
Skeletal muscle is a notoriously difficult tissue to study. Muscle fibers are large, multinucleated cells that are hard to grow, image, and manipulate experimentally. Many techniques that work well in other cell types are much more challenging to apply in muscle, and developing treatments for muscle disorders remains a major hurdle.
Over the years, I have learned that "impossible" often just means that the right tools or approaches have not been developed yet. Once you have them, questions that once seemed out of reach can suddenly become answerable. That experience has taught me not to be discouraged by difficult problems. In fact, when something seems especially hard, I often wonder whether it is because we are looking at something genuinely new.
Q | If your research succeeds, what could it change for science or society?
In my opinion, research is already a success when it expands our understanding of the world. Today, there is often an expectation that scientific discoveries should quickly translate into benefits for human health or society. While that is an important goal, many of the greatest breakthroughs have come from scientists simply being curious and asking questions without knowing where the answers would lead, or even by chance—just look at how PCR was invented by Kary Mullis.
One of the things I value most about being a scientist is the freedom to ask questions and follow the data, even when there is no obvious application in sight. At the same time, I hope my work will have a long-term impact. If my research succeeds, it will help us better understand how skeletal muscle develops, how individual muscle fibers are formed through cell-cell fusion, and how they withstand the repeated mechanical forces generated during contraction. I also hope to provide new techniques and experimental approaches that scientific communities can use to answer their own questions.
Q | What question are you most excited to answer next?
In my experience, the next research questions are usually generated by the answers to the current ones. Right now, I am excited to further develop my work on how nuclei in muscle cells cope with the mechanical stress generated by repeated contractions, particularly focusing on DNA damage and the signaling pathways that help cells respond to and repair it.
Responses have been edited for length and clarity.
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