An international study coordinated by the Department of Translational Medicine identifies Vitamin D-Binding Protein as a potential therapeutic target to counteract muscle loss in cancer patients.
A study recently published in the prestigious journal Nature Communications sheds new light on the molecular mechanisms of cachexia, a severe metabolic syndrome affecting many patients with cancer or chronic diseases, causing progressive and debilitating loss of muscle mass and strength.
The study—led by Professor Nicoletta Filigheddu and Dr. Tommaso Raiteri from DIMET, in collaboration with colleagues from the UPO Department of Health Sciences, the University of Turin, the IEO in Milan, and Stony Brook University (New York)—has identified a new “piece of the puzzle”: Vitamin D-Binding Protein (VDBP).
Until now, VDBP was primarily known for its role in transporting Vitamin D through the blood. However, researchers observed that levels of this protein increase significantly in patients with cachexia. Through experimental models, the team demonstrated that VDBP acts as a genuine “pro-atrophic hormone“.
The most significant finding is that this effect occurs independently of Vitamin D levels. VDBP interferes with actin dynamics within muscle cells, causing oxidative stress and fragmentation of mitochondria (the cells’ energy powerhouses), leading to muscle wasting.
The research demonstrated that the absence of this protein protects against muscle function loss induced by tumors. This makes VDBP a promising therapeutic target: targeting this protein could, in the future, allow for the development of specific treatments to counteract muscle atrophy, drastically improving the quality of life and treatment response for oncology and chronic patients.
This work was supported by the 2023-2027 Department of Excellence and Age-IT programs.
https://pubmed.ncbi.nlm.nih.gov/41963327/
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Three Questions For Nicoletta Filigheddu
Associate Professor of Advanced Medical and Surgical Technical Sciences at the Department of Translational Medicine, University of Eastern Piedmont (UPO).
- Why is this discovery considered a breakthrough compared to what we already knew about Vitamin D and the VDBP protein?
“Vitamin D has long been known for its protective effect on skeletal muscle. For this reason, when an increase in its transport protein (VDBP) is observed in conditions associated with muscle loss, the most immediate interpretation has been that VDBP ‘sequesters’ Vitamin D, reducing its availability and beneficial effects.
Our discovery represents a breakthrough because it challenges this very framework. We have shown that, in the context of skeletal muscle, VDBP is not just a transporter but a biologically active molecule with its own effects. Specifically, VDBP can induce muscle atrophy even when Vitamin D levels are unaltered. This shift in perspective is crucial as it opens new therapeutic possibilities: rather than just correcting Vitamin D levels, we may need to intervene directly on VDBP or the mechanisms through which it damages the muscle”.
- Can you explain in simple terms how this protein causes the loss of muscle mass and strength?
“VDBP causes muscle loss by exploiting its lesser-known ability to bind actin, a protein that constantly transitions between a globular state (G-actin) and a polymerized filamentous state (F-actin). This dynamic balance is essential for cell shape, movement, and mitochondrial function.
Normally, VDBP acts as a ‘scavenger’ to capture actin if it is released outside the cell (e.g., following trauma) to prevent blood vessel obstruction. However, when VDBP enters the muscle cell, it binds to globular actin and disrupts the internal balance, triggering a cascade that compromises the mitochondria. When mitochondria fail, the muscle cell produces less energy and generates harmful byproducts that lead to a reduction in mass and strength”.
- What are the next steps for the research, and how close are we to a potential therapeutic approach for patients?
“The next steps involve identifying the most effective point of intervention: whether ‘upstream’ by preventing excessive VDBP production, or ‘downstream’ by blocking its entry into muscle cells or its interaction with intracellular actin.
However, we must be realistic: while our results are robust, we are still in a preclinical stage. Developing a therapeutic approach for patients will require several more years of research”.
