This pathological process, characterized by the replacement of functional cells with the accumulation of connective tissue, is associated with a broad spectrum of chronic or low-prevalence syndromes, including pulmonary fibrosis, muscular dystrophies, or liver fibrosis.

With the aim of understanding the mechanisms that contribute to its development, the study detected a pathway called YAP/TAZ, whose inhibition managed to reduce the fibrotic response.

A team of Chilean and international researchers has identified a new therapeutic target to treat fibrosis, with a special focus on muscle fibrosis, a common problem in diseases such as muscular dystrophies, sarcopenia, and other neuromuscular disorders.

This finding, led by Dr. Enrique Brandan of the Centro Basal Ciencia & Vida (FCV-USS), was recently published in the journal American Journal of Physiology-Cell Physiology and represents a significant advance in understanding the mechanisms that lead to this response in muscle tissue.

Fibrosis is a pathological process present in a vast number of chronic pathologies (according to the scientists responsible for the study, there could be more than 60) and is characterized by the excessive accumulation of connective tissue in response to the loss of functionality in the affected organs.

This process occurs in response to persistent inflammation, abnormally activating fibroblasts, which produce an excessive accumulation of extracellular matrix. Over time, fibrosis can lead to irreversible tissue damage and affect essential functions such as respiration, blood filtration, or muscle mobility.

“Current research suggests that fibrosis is not an isolated process, but rather a response of the body to various factors, such as cellular damage or inflammation, which ends up replacing functional tissue with non-functional connective tissue. What we discovered is that tissue stiffness, whether due to mechanical factors or pathological processes, activates a signaling pathway called YAP/TAZ, which accelerates the fibrotic response in the body,” explains Dr. Brandan.

The study's main objective was to understand the molecular and cellular pathways that trigger this fibrotic response. Disorders related to this mechanism are involved in some of the leading causes of mortality worldwide, emphasizing the importance of further deepening our understanding to search for new treatments or preventive strategies.

The activation of YAP/TAZ

Muscle fibrosis occurs when functional muscle tissue is replaced by non-functional connective tissue, decreasing its capacity for contraction and regeneration. This occurs in response to persistent damage or chronic inflammation, abnormally activating muscle fibroblasts, which generate an excessive accumulation of extracellular matrix. Over time, this process limits mobility, reduces strength, and affects patients' quality of life.

The researchers identified that muscle tissue stiffness and other pathological factors activate a signaling pathway called YAP/TAZ. This molecular pathway acts as a control center where different signals inducing fibrosis converge, functioning as a “switch” that accelerates the formation of scar tissue in the muscle.

Dr. Brandan explains that this pathway functions as a command center where many different signals converge. In this logic, if intervened, it could be possible to block the development of muscle fibrosis regardless of the initial trigger. “Although our research has focused mainly on a model of muscular dystrophy, the results obtained have much broader implications, as the mechanisms we have identified could also apply to the treatment of chronic diseases in other organs, such as the heart, lungs, or kidneys.”

In the case of pulmonary fibrosis, for example, the functional tissue of the lung is gradually replaced by a connective or “scar” type, interfering with the organ's ability to function normally and, consequently, affecting patients' lives. Or, as in cardiac infarctions, where the region that loses functionality after the event is replaced by rigid tissue, which decreases the heart's ability to pump blood.

The reduction of fibrosis

The study demonstrated that inhibiting YAP/TAZ activity significantly reduces fibrosis in experimental models of muscle diseases. It was observed that blocking this pathway decreases collagen accumulation and better preserves muscle functionality. This could become an effective therapeutic strategy for diseases such as Duchenne muscular dystrophy, sarcopenia, and other fibrotic myopathies.

A key element in the activation of this pathway is the TGF-beta protein, which regulates cell proliferation and differentiation in the muscle. Under fibrotic conditions, TGF-beta is overexpressed, activating fibroblasts and promoting extracellular matrix accumulation. However, due to its involvement in other essential cellular processes, directly inhibiting TGF-beta is not viable as a treatment.

In this context, node inhibition appears as a more specific and safer alternative to treat muscle fibrosis. Observations were made in both experimental and cellular models, with similar results, in addition to the use of advanced molecular analyses and multidisciplinary collaborations. “Inhibition of the YAP-TAZ pathway not only blocks a specific signal, but also has broader effects on the cellular pathways involved in fibrosis, making this intervention promising for treating not only muscle diseases, but also pulmonary, cardiac, and muscular diseases.”

“We believe that the inhibition of this signaling pathway is one of the most promising interventions we have identified, as it not only acts by blocking a key molecular pathway, but also has effects on other mechanisms involved in fibrosis,” states the academic from the Centro Basal Ciencia & Vida (FCV-USS).

Clinical implications and future research

The results of this research could have a significant impact on medicine, as muscle fibrosis is a key factor in many debilitating diseases. “When there is a muscle disease, one alternative is to fight fibrosis. If we manage to reduce it, we can lessen the loss of mobility and strength in patients,” points out Dr. Brandan.

The research team highlights that this finding is the result of multidisciplinary work, with Dr. Andrea Ravasio from the Faculty of Engineering of the Pontificia Universidad Católica de Chile and the use of experimental models, human tissues, and advanced molecular analyses.

In the future, they hope to continue exploring ways to modulate YAP/TAZ with greater precision to develop more effective and safer therapies, in order to strengthen basic science knowledge, which is fundamental both for understanding pathologies and for designing new therapeutic alternatives.

With this discovery, a new avenue opens up to address fibrosis from its molecular regulation, offering hope for the treatment of chronic and neuromuscular diseases that until now lack effective solutions, concludes Dr. Brandan.