When a motor nerve loses contact with a muscle due to injury, neuromuscular disease, or aging, the muscle tissue does not just weaken: it also fills with scar tissue. This process, called fibrosis, is irreversible in advanced stages and is characteristic of pathologies as distinct as liver cirrhosis, pulmonary fibrosis, or diabetic nephropathy. Although molecular mediators of fibrosis are known, such as TGF-β or CTGF/CCN2, none of a lipid nature had been identified in skeletal muscle.

A team of Chilean researchers has just filled that gap. Dr. Enrique Brandan, leader of the research group, principal investigator at the Centro Ciencia & Vida, Director of Research at the Faculty of Medicine of the Universidad San Sebastián, and an academic at that institution, led a study published in JCI Insight that identifies lysophosphatidic acid (LPA) as the first lipid mediator that triggers muscle fibrosis following the loss of innervation.

The work brought together 15 specialists from Chilean institutions, with the participation of Dr. Jerold Chun, a world leader in LPA signaling and neurological diseases, from the Sanford Burnham Prebys Medical Discovery Institute in California.

LPA is a bioactive lipid with a simple structure that normally regulates basic cellular processes, but in the absence of nerve signaling, it acts as an orchestrator of muscle tissue destruction. What distinguishes this finding is that the fibrosis mediators known until now were proteins or peptides; LPA opens a pharmacological path different from the one that had been explored.

"The vast majority of fibrosis mediators are proteins or peptides. What we have found is a lipid, a different molecule. People never look at the lipid, and here it is a lipid that directly triggers the fibrotic response," explains Brandan.

The first authors of the study are Meilyn Cruz-Soca, a researcher trained at the USS and the Centro Ciencia & Vida, and Adriana Córdova-Casanova.

The lipid that ignites muscle scarring

LPA acts through a signaling chain that involves a producing enzyme, autotaxin, and specific cellular receptors, particularly the LPA₁ receptor. When the nerve loses contact with the muscle, LPA levels increase in the tissue and activate two proteins that function as genetic switches within the cells: YAP and TAZ. These order a special type of muscle cell, fibro/adipogenic progenitors or FAPs, to proliferate and produce scar tissue in excessive amounts.

The team demonstrated that the mechanism does not require a severe injury. Even a transient nerve compression, such as what can occur in early stages of ALS or in trauma, is enough to activate the LPA/YAP/TAZ axis and trigger a fibrotic response. The implication is that tissue damage begins before the disease is clinically evident.

The study also includes a direct genetic demonstration, made possible through the mediation of Dr. Moisés Selman, Director of Research at the National Institute of Respiratory Diseases of Mexico, who facilitated access to LPA₁ KO mouse models. Animals lacking that receptor that underwent surgical denervation (when the muscle loses its connection to the motor nerve) showed significantly less fibrosis than controls, in what Brandan describes as a "direct proof" that LPA acts specifically through that pathway and not non-specifically on the tissue.

To complete the map of the mechanism, the laboratory also tested inhibitors of YAP and TAZ, the effector proteins downstream of LPA, with the same effect: reduction of scar tissue. This confirms that the axis operates as a functional chain that can be interrupted at different points. "Either you inhibit LPA production by blocking the autotaxin enzyme, or you inhibit LPA action by blocking its receptors. In both cases, you see the same effect: the fibrotic response is inhibited. That is the axis," points out the USS academic.

The relevance of this duality is pharmacological: there are inhibitors available for both targets, which expands the options for clinical development and allows the therapeutic strategy to be adapted according to the patient's or disease's profile.

From experimental blockade to therapeutic target

In denervation models, the inhibitor Ki16425, which blocks the LPA₁ receptor, not only reduced the accumulation of scar tissue but also protected the integrity of the sciatic nerve and improved reinnervation signals at the neuromuscular junction. This dual effect, on the muscle and on the nerve, expands the clinical relevance of the finding. In parallel, the team is working on a new report that extends these results to models of muscular dystrophy, including Duchenne muscular dystrophy and sarcoglycanopathy, in which blocking the LPA axis reduced scarring and improved muscle strength.

If confirmed, that work would add a second proof of concept in conditions of greater clinical prevalence. "If you take those three pieces of evidence: the injection into the muscle, the blockade in denervation, and the blockade in dystrophy, this axis becomes a potential axis with therapeutic characteristics," explains Dr. Brandan.

The pharmacological importance is reinforced by recent advances: LPA₁ receptor inhibitors are already in phase 2 clinical trials for idiopathic pulmonary fibrosis, which means that part of the safety and tolerability work is already advanced, shortening the path toward an eventual application in neuromuscular diseases. "Phase 1 is probably not necessary, because these inhibitors have already been used in other fibroses, such as renal or hepatic, so we could go directly to a phase 2," adds the researcher.

And although his laboratory has transferred findings that have fostered biotechnological advances, Brandan warns that moving forward with a process of this magnitude from Chile is "unrealistic." "Chile invests 0.41% of its GDP in science, far from the 1% committed to by successive governments, and that gap makes conducting a trial of that scale locally unfeasible."

A mechanism shared by 64 chronic diseases

Fibrosis is not a phenomenon exclusive to muscle. It is the shared outcome of dozens of chronic diseases, from liver cirrhosis to diabetic nephropathy, including pulmonary fibrosis and ischemic heart disease. What varies between them is the organ and the initial cause; the final process, the replacement of functional tissue with scar tissue, is the same. "Millions of patients suffer from these chronic conditions, which are a great burden on health systems," describes Brandan.

Advanced pulmonary fibrosis leaves lung transplantation as the only option. Terminal cirrhosis requires a liver transplant. Diabetic nephropathy, one of the leading causes of chronic kidney failure, often ends in dialysis or kidney transplantation. In all those tissues, other teams have demonstrated the involvement of LPA. The biology of the lipid, in Brandan's words, “is not a unique thing to muscle.”

This transversal logic guides the laboratory's agenda. Muscle was the entry model, the terrain in which the team has decades of experience, but the search points to broad-spectrum inhibitors. Gene therapies for muscular dystrophies, which address the primary cause of the disease, can cost up to 4 million dollars per patient. Reducing associated fibrosis does not replace those treatments, but it improves the muscle environment and can enhance their efficacy, at a potentially much lower cost.

"What one must aspire to is finding simpler, more straightforward drugs that can eventually have lower costs. Fibroses are not rare diseases: millions of people with chronic conditions like diabetes, hypertension, or cirrhosis have them," concludes Brandan.

Text by Luis Francisco Sandoval, Agencia S&M Comunicaciones.