Early inhibition of the ATX-LPA axis modulates YAP/TAZ signaling and mitigates dystrophic progression in δ-SACOGLYCANOPATHY mice
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2025
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Abstract
Sarcoglycanopathies, a type of limb girdle muscle dystrophy, are caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma. This leaves muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses, resulting in muscle weakness and atrophy. In different tissues, two signaling pathways have been implicated in inflammation and fibrosis: autotaxin-lysophosphatidic acid (ATX-LPA) and yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ). LPA, synthesized by ATX, can act as a pleiotropic molecule due to its multiple receptors. The two Hippo pathway effectors, YAP/TAZ, can be dephosphorylated by LPA and translocated to the nucleus. They induce several target genes, such as CCN2/CTGF, involved in fibrosis and inflammation. However, no detailed characterization of these processes and pathways in the development of sarcoglycanopathy or the effect of early inhibition of this axis has been evaluated in skeletal muscle.Using the δ-sarcoglycan knockout mouse model (Sgcd-/-), the study investigated components of these pathways, muscle regeneration, inflammatory and fibrotic responses, and muscle function of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) during the development of δ sarcoglycanopathy in the first two months of life. In addition, the effect of early ATX-LPA axis inhibition on inflammatory profile, ECM component deposition, muscle function and regenerative capacity was evaluated using PF8380 (ATX inhibitor) and Ki16425 (LPA1 antagonist). Sgcd-/- mice showed early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, and regenerated fibers) followed by later fiber size reduction in TR, GST, and DFG. These changes are concomitant with an early inflammatory and fibrotic response in these muscles. Early impairments in force generation in the TA and EDL, resistance to mechanical damage in the EDL, and running ability were also observed in these mice. Furthermore, these animals showed early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the muscles. Interestingly, inhibition of the ATX-LPA axis with either inhibitor modulated YAP/TAZ signaling, ameliorated the inflammatory and fibrotic response in the muscle studied, and improved muscle performance and running ability in Sgcd-/- mice.This study provides compelling evidence that the ATX-LPA axis and YAP/TAZ signaling pathway are dysregulated in skeletal muscle of Sgcd-/- mice from an early age. These molecular alterations coincide with the development of fibrotic and inflammatory responses in this disease model. Importantly, our findings demonstrate that targeted inhibition of either ATX or LPA1 results in significant amelioration of these pathological processes. These results not only advance our understanding of the molecular mechanisms underlying muscular dystrophy but also identify the ATX-LPA axis as a promising therapeutic target for intervention.
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Tesis (Doctor en Ciencias Médicas)--Pontificia Universidad Católica de Chile, 2025