Research Highlight: Q&A with Dr. Daniel Ham

Each month, we delve into the scientific literature to uncover standout uses of our technology and spotlight the remarkable work emerging from the research community. From neuroscience and nociception to skeletal muscle physiology and cardiology, we carefully curate themed publication highlights that offer concise, pertinent overviews of cutting-edge studies.

Every now and then, a paper does more than pique our interest: it compels us to take a closer look. Such was the case with a recent publication in Nature Communications: “Muscle fiber Myc is dispensable for muscle growth and its forced expression severely perturbs homeostasis” by Ham et al (2025). Featured in our April review, ‘Fueling Function: Forthcoming Insights in Muscle Physiology’, this study stood out for its scientific rigor and for the provocative questions it raises about muscle regulation and growth.

We knew a brief summary wouldn’t do the work justice. The study called for a deeper exploration that unpacked the experimental nuances and the motivations behind the research. So, we reached out directly to the first author, Dr. Daniel Ham, who generously shared his time and insights in an in-depth Q&A. What followed was a compelling conversation that offers a behind-the-scenes look at the study’s conception, execution, and implications for the broader field of muscle biology. Dr. Ham’s reflections on his scientific journey and his vision for future research make this exchange a must-read for anyone invested in muscle science.

Join us as we dig into the story behind the science.

Dr. Ham cites his undergraduate research project, which focused on fatigue mechanisms in cyclists, as the catalyst for his scientific career.

Q: What is your background (where did you grow up, what subjects interested you in school, etc.) and how did this develop your passion for science? 

Dr. Ham: I grew up in rural Australia and attended high school in a small regional city called Warrnambool, located at the end of the Great Ocean Road. Most people think of Australia as hot and sunny, but Warrnambool is cold, windy and wet for much of the year. At school, I enjoyed both maths and sport and wanted to somehow combine the two professionally. I was initially studying to become a physical education and maths teacher, but was exposed to research while doing an undergrad project focused on fatigue mechanisms in cyclists. I was fascinated by the way so many different physiological factors interacted to determine performance, and being able to measure them meant I could test my own (sometimes misguided) theories. After this project, I took up cycling as a hobby and was hooked on science as a career.

Q: Could you walk us through your scientific journey up to your current position at the University of Basel? What drew you to Dr. Markus Rüegg’s lab? 

Dr. Ham: I continued working on human performance, but this time in the context of assessing readiness for physically demanding work tasks with the Australian Defence Force. I was then fortunate to be offered the opportunity to pursue a PhD at the University of Melbourne with Professors Gordon Lynch and René Koopman. I wanted to understand whether nutrients, specifically amino acids, could blunt muscle loss under various wasting conditions. At the time, essential amino acids were seen as a potential intervention for muscle wasting conditions based on their activation of protein synthesis and ability to enhance muscle growth during resistance training. Amino acids, especially leucine, activate the mammalian target of rapamycin complex 1 (mTORC1), which increases protein synthesis and inhibits breakdown via autophagy. However, while working on a literature review, I became skeptical that direct activation of mTORC1 would promote muscle growth. Key to my shift in thinking was a paper from the Rüegg lab, which showed that constant activation of mTORC1 did not lead to bigger and stronger muscles as expected, but rather caused atrophy and muscle dysfunction. I really related to the way the lab was willing to shift its position and challenge the prevailing notion that mTORC1 activation promotes muscle growth. So, when the opportunity arose to study the role of mTORC1 activity in muscle aging in the Rüegg lab, I jumped at the chance.

Q: Was there a specific experiment or observation early on that made you think Myc might not be as central to muscle hypertrophy as previously thought?

Dr. Ham: As the muscles of mice lacking Myc in muscle fibers continued to grow normally under multiple conditions, so did our doubts that Myc was important for muscle fiber hypertrophy. But for me, it was actually the strikingly negative effects of Myc depletion on muscle stem cell function that really cemented my thinking. The stark contrast between the effects of Myc depletion in muscle stem cells compared to muscle fibers highlighted the central role Myc can play in the growth of certain cells, but also reassured us that Myc could be efficiently depleted in our floxed Myc mice.

Q: Given Myc’s notorious reputation in cancer biology, how did its role in skeletal muscle become an area of interest for your team?

Dr. Ham: In fact, Myc’s notoriety in cancer cell growth was one of the reasons we were interested in studying its role in muscle growth. Myc gain-of-function promotes malignant transformation and supports rapid growth in many cancer cells, but muscle fibers are terminally differentiated, meaning they cannot proliferate and cannot become cancerous. So, the same signals driving unwanted growth in cancer cells can instead mediate desirable growth in muscle. A great example is the Akt-mTORC1 pathway. Myc expression is also high in growing muscles and was thought to support growth by stimulating the biogenesis of ribosomes, which synthesize proteins.

Q: How did you go about designing your experiments and what sort of methodologies did you feel were important to ascertain the answer to your research question(s)?

Dr. Ham: Since the primary role of muscle is to produce force, and the largest contributor to force production is the size of the muscle, the vast majority of my experiments are designed to capture the effect of an intervention on the muscle’s size and its capacity to produce force. We routinely use ex-vivo preparations of extensor digitorum longus and soleus muscles, representing fast- and slow-twitch muscles, to measure functional properties. We couple this with muscle mass and type-specific fiber size measurements. These outcome measures give the essential context for changes in signaling to be interpreted.

Q: One of your most striking findings is that Myc overexpression in myofibers leads not to hypertrophy, but to dysfunction. How did you first react to these unexpected results?

Dr. Ham: By the time we conducted this experiment, we were already open to the possibility that muscle fibers would not respond well to Myc overexpression. However, we were still shocked by how rapidly and severely the muscles of these mice deteriorated. In a pilot study, we first noticed that mice started looking unwell just two weeks after beginning tamoxifen treatment, which induced expression of the Myc transgene. We were initially concerned that something had gone wrong with our tamoxifen administration, but when we checked genotypes, it became clear that only mice with the Myc transgene were affected, while control mice remained healthy. For subsequent experiments, we shortened our treatment times and were still surprised to see measurable reductions in muscle force just four days after tamoxifen administration.

Representative image (courtesy of Daniel Ham) of eGFP+ fibers in longitudinal sections from Pax7-MycTG mice, 28 days after nerve crush (fibers in green, nuclei in magenta).

Q: You describe a “de-differentiation-like” effect caused by Myc overexpression. Do you think Myc is actively reprogramming mature myofibers toward a progenitor-like state?

Dr. Ham: That’s a great question. Based on the strong repression of mature muscle fiber genes, which encode for proteins that allow muscle to produce force, along with the suppression of some cell cycle inhibitors that help maintain their terminally differentiated state, it appears that Myc overexpression is at least pushing muscle fibers in the direction of a progenitor-like state. Myc is one of the four ‘Yamanaka factors’ used to generate induced pluripotent stem cells from differentiated human cells. Although muscle fibers are considered terminally differentiated, under some experimental settings, such as when cell cycle inhibitors are suppressed, myotubes are actually capable of re-entering the cell cycle. However, they fail to fully replicate their DNA, and to my knowledge, a fully differentiated mammalian muscle fiber is yet to be reprogrammed sufficiently to become proliferation-competent. Interestingly, muscle fibers from newts can return to a progenitor state during limb regeneration, but only after breaking down into mononucleated cells, effectively destroying the muscle before proliferating to support regeneration. Based on the rapid loss of muscle structure and function we observed, our experiments suggest that Myc overexpression may trigger a de-differentiation-like breakdown of muscle fibers in mammalian muscle, which may explain why Myc expression is very low in mature muscle fibers.

Q: What implications do your findings have for muscle-wasting diseases and interventions? 

Dr. Ham: Understanding the mechanisms that regulate muscle size is paramount to identifying interventions to target muscle wasting conditions. Based on previous evidence, research efforts had justifiably focused on boosting Myc expression, which was expected to promote muscle fiber hypertrophy. Our work adds important specificity to Myc’s role in regulating muscle growth. While Myc is essential in muscle stem cells for their contribution to muscle growth, Myc expression in muscle fibers is not helpful for growth and is likely harmful.

Q: What do you hope other scientists take away from this paper? 

Dr. Ham: I hope that this paper will help provide important context for interpreting changes in Myc expression within muscle in future studies. I also think it highlights the importance of localizing changes in Myc expression to specific cell types, such as muscle fibers, muscle stem cells, and other muscle resident mono-nucleated cells.

Q: This study spans molecular genetics, physiology, and transcriptomics. How did you navigate such interdisciplinary territory as a team?

Dr. Ham: The biological sciences are becoming increasingly interdisciplinary. Being part of a strong, diverse team within a supportive institute really helps remove barriers to interdisciplinary research. At the Biozentrum in Basel, we benefit from excellent core facilities, and there is always someone in the building with the specific skills and expertise needed to fill any knowledge gaps.

TA cross-sections of control and 10 d HSA-MycTG mice (adapted from ©Ham et al (2025), licensed under CC BY 4.0). The H&E staining (left) shows severe degeneration, including atrophic and necrotic fibers with immune cell infiltration while IgG staining (right) confirms compromised muscle fiber integrity, absent in control tissue.

Q: Looking back, what was the most difficult moment in the project, and how did you overcome it?

Dr. Ham: The most challenging point was when it became clear that Myc didn’t play a major role in muscle fiber growth. Proving a negative is inherently difficult, especially when it contradicts the prevailing view. A clear effect of an intervention is straightforward to interpret, but when we saw no effect of Myc depletion, we had to closely scrutinize our methods and experimental conditions. We thought a lot about how to approach this before settling on three key approaches to provide the strongest evidence that Myc expression in muscle fibers does not support muscle growth. Firstly, we wanted to demonstrate that depleting Myc in a proliferative cell type, using the same Cre-Lox system, would impair its growth. We targeted muscle stem cells, which support muscle regeneration and contribute to certain forms of muscle growth. Myc depletion severely blunted the contribution of muscle stem cells to muscle growth and regeneration. Secondly, we wanted to confirm that even with extreme hypertrophy, Myc expression was not required. To test this, we crossed Myc knockout mice with a line that allowed tamoxifen-inducible Akt activation in muscle fibers. In several muscles, mass increased by over 70% in just two weeks. This growth occurred regardless of Myc depletion. Thirdly, we wanted to confirm that forced Myc expression in muscle fibers would not cause growth. As you noted, this experiment produced one of the most striking observations of the study. Myc overexpression did not cause growth but instead severely impaired muscle structure and function. Together, these experiments gave us a positive control for our model and showed that Myc expression in muscle fibers was not necessary or sufficient to promote muscle growth.

Q: What are your current and future research interests?

Dr. Ham: I am interested in what makes muscles weaker as we age. It happens to all of us, no matter what we eat or how much we exercise and has a big impact on how long we can maintain our independence. I want to better understand how this happens so we can find better ways to maintain our muscle function as we age. There are indications that Myc expression also increases in old muscles. Given the strong detrimental effects of Myc overexpression on muscle function, we are currently interested in whether elevated Myc expression contributes to muscle aging.

As we conclude this Q&A-style research highlight, we’re reminded of the power of research to reshape scientific assumptions and ignite new avenues of inquiry. Dr. Ham’s work challenges long-held notions about muscle fiber Myc and also exemplifies the kind of thoughtful, boundary-pushing research that drives the field forward. His insights offer a rare window into the scientific process: equal parts curiosity, rigor, and persistence. We’re grateful for the opportunity to share this conversation and look forward to spotlighting more such contributions in the months ahead.

Until then, stay curious and keep exploring the science that moves us.