Blocking LPA Signaling Cuts Muscle Fibrosis After Nerve Injury in Mice

Skeletal muscle fibrosis is a debilitating consequence of nerve injury and chronic neuromuscular diseases such as ALS, Duchenne muscular dystrophy, and diabetic neuropathy. Excessive extracellular matrix (ECM) deposition stiffens muscle, impairs contractile function, and undermines the effectiveness of cell and gene therapies. Despite this clinical importance, the upstream lipid mediators that initiate and sustain muscle fibrosis after denervation have been poorly understood. This study, published in JCI Insight, provides the first mechanistic demonstration that endogenous lysophosphatidic acid (LPA) signaling through LPA receptor 1 (LPA1) and the downstream transcriptional coactivators YAP and TAZ constitutes a central fibrogenic axis in denervated skeletal muscle.

Using the well-established sciatic nerve transection model in mice, the investigators first mapped the regulation of the entire LPA signaling axis at 4 days and 2 weeks post-denervation in gastrocnemius (GST) muscles. Four of six LPA receptors (Lpar1, Lpar2, Lpar3, Lpar6) were transcriptionally upregulated in denervated versus contralateral muscles. Simultaneously, the LPA-synthesizing enzyme autotaxin (ATX/Enpp2) was downregulated at both mRNA and protein levels, while LPA-degrading enzymes (Plpp1–3) were upregulated — a seemingly paradoxical pattern explained by direct ELISA measurement of intramuscular LPA. LPA concentrations were significantly elevated in denervated GST muscle at 2 days post-denervation compared with non-operated controls and sham-operated muscle, returning to baseline by day 4. This transient early LPA pulse, despite subsequent upregulation of degrading enzymes, suggests a rapid, burst-like lipid signal that initiates downstream fibrogenic cascades.

To establish causality, the team used two complementary strategies. First, pharmacological inhibition of LPA1/3 with Ki16425 (administered intraperitoneally from 3 days before denervation through 2 weeks after) significantly reduced fibronectin (Fn1), collagen I (Col1a1), and CCN4 mRNA levels, and decreased fibronectin and CCN2 protein accumulation by Western blot and immunofluorescence, as well as total collagen by Sirius red staining in denervated muscle. Second, genetic deletion of Lpar1 (Lpar1-KO mice) recapitulated these findings — denervated KO mice showed lower Fn1 and Col1a1 mRNA, reduced fibronectin and CCN2 protein, and less collagen deposition than wild-type littermates — confirming that LPA1 is the primary receptor driving denervation-induced muscle fibrosis.

Mechanistically, the study examined the role of fibro/adipogenic progenitors (FAPs) and the YAP/TAZ pathway. Denervation expanded the FAP population (marked by PDGFRα and Sca-1), and this expansion was significantly blunted by Ki16425 or Lpar1 knockout. In denervated muscle, YAP and TAZ protein expression increased, and both coactivators accumulated in FAP nuclei — indicating transcriptional activation — an effect attenuated by LPA axis blockade. Consistent with a functional role, pharmacological inhibition of YAP/TAZ with verteporfin reduced fibrotic marker expression after denervation, supporting YAP/TAZ as essential downstream mediators of LPA1-driven muscle scarring. Notably, while LPA blockade suppressed atrophy-related gene expression (including MuRF-1 and MAFbx), it did not fully preserve myofiber cross-sectional area, suggesting that atrophy and fibrosis are partially dissociable downstream of LPA signaling.

A particularly clinically relevant finding came from the nerve crush model, which induces transient denervation followed by reinnervation. Even this milder, recoverable injury was sufficient to activate the LPA axis, trigger FAP expansion, promote ECM deposition, reduce axonal density in the sciatic nerve, and increase neuromuscular junction (NMJ) instability (assessed by the ratio of denervated to innervated NMJs). Ki16425 treatment reversed all of these effects, suggesting that LPA signaling not only drives muscle fibrosis but also impairs peripheral nerve regeneration and NMJ stability. This bidirectional relationship between LPA-driven fibrosis and nerve integrity opens a novel therapeutic angle: blocking LPA1 may simultaneously reduce scar tissue and improve the conditions for nerve regrowth and reinnervation, with implications for ALS, muscular dystrophies, traumatic nerve injuries, and age-related sarcopenia with denervation.