Dysregulated ATX-LPA and YAP/TAZ signaling in dystrophic Sgcd−/− mice with early fibrosis and inflammation

Abstract

Background: Sarcoglycanopathies are muscle dystrophies caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma, leaving muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses and resulting in muscle weakness and atrophy. Two signaling pathways have been implicated in fibrosis and inflammation in various tissues: 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. 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 or whether these pathways change early in the development of sarcoglycanopathy has been evaluated in skeletal muscle. Methods: Using the δ-sarcoglycan knockout mouse model (Sgcd−/−), we investigated components of these pathways, inflammatory and fibrotic markers, and contractile properties of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) at one and two months of age. Results: We found that Sgcd−/− mice show early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, inflammatory infiltrate, 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. Sgcd−/− mice also have early impaired force generation in the TA and EDL, and resistance to mechanical damage in the EDL. In addition, an early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the TR, GST, and DFG was observed in these mice. Conclusions: The ATX-LPA axis and the YAP/TAZ signaling pathway, which are involved in inflammation and fibrosis, are dysregulated in skeletal muscle from an early age in Sgcd−/− mice. These changes are concomitant with a fibrotic and inflammatory response in these mice. Unraveling the role of the LPA axis and YAP/TAZ in sarcoglycanopathy holds great promise for improving our understanding of disease pathogenesis and identifying novel therapeutic targets for this currently incurable group of muscle disorders.

Abstract Background: Sarcoglycanopathies are muscle dystrophies caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma, leaving muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses and resulting in muscle weakness and atrophy. Two signaling pathways have been implicated in fibrosis and inflammation in various tissues: autotaxin/lysophosphatidic acid (ATX-LPA) and yes-associated protein 1/transcriptional co-activator with PDZbinding motif (YAP/TAZ). LPA, synthesized by ATX, can act as a pleiotropic molecule due to its multiple receptors. Two Hippo pathway effectors, YAP/TAZ, can be dephosphorylated by LPA and translocated to the nucleus. They induce several target genes, such as CN2/CTGF, involved in fibrosis and inflammation. However, no detailed characterization of these processes or whether these pathways change early in the development of sarcoglycanopathy has been evaluated in skeletal muscle. Methods: Using the δ-sarcoglycan knockout mouse model (Sgcd−/−), we investigated components of these pathways, inflammatory and fibrotic markers, and contractile properties of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) at one and two months of age. Results: We found that Sgcd−/− mice show early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, inflammatory infiltrate, 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. Sgcd−/− mice also have early impaired force generation in the TA and EDL, and resistance to mechanical damage in the EDL. In addition, an early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the TR, GST, and DFG was observed in these mice. Conclusions: The ATX-LPA axis and the YAP/TAZ signaling pathway, which are involved in inflammation and fibrosis, are dysregulated in skeletal muscle from an early age in Sgcd−/− mice. These changes are concomitant with a fibrotic and inflammatory response in these mice. Unraveling the role of the LPA axis and YAP/TAZ in sarcoglycanopathy holds great promise for improving our understanding of disease pathogenesis and identifying novel therapeutic targets for this currently incurable group of muscle disorders.