Aberrant adenosine triphosphate release and impairment of P2Y2-Mediated signaling in sarcoglycanopathies

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Item Type:	Article
Title:	Aberrant adenosine triphosphate release and impairment of P2Y2-Mediated signaling in sarcoglycanopathies
Creators Name:	Benzi, A., Baratto, S., Astigiano, C., Sturla, L., Panicucci, C., Mamchaoui, K., Raffaghello, L., Bruzzone, S., Gazzerro, E. and Bruno, C.
Abstract:	Sarcoglycanopathies, limb-girdle muscular dystrophies (LGMD) caused by genetic loss-of-function of the membrane proteins sarcoglycans (SGs), are characterized by progressive degeneration of skeletal muscle. In these disorders, muscle necrosis is associated with immune-mediated damage, whose triggering and perpetuating molecular mechanisms are not fully elucidated yet. Extracellular adenosine triphosphate (eATP) seems to represent a crucial factor, with eATP activating purinergic receptors. Indeed, in vivo blockade of the eATP/P2X7 purinergic pathway ameliorated muscle disease progression. P2X7 inhibition improved the dystrophic process by restraining the activity of P2X7 receptors on immune cells. Whether P2X7 blockade can display a direct action on muscle cells is not known yet. In this study, we investigated eATP effects in primary cultures of myoblasts isolated from patients with LGMDR3 (α-sarcoglycanopathy) and in immortalized cells isolated from a patient with LGMDR5 (γ-sarcoglycanopathy). Our results demonstrated that, owing to a reduced ecto-ATPase activity and/or an enhanced release of ATP, patient cells are exposed to increased juxtamembrane concentrations of eATP and display a higher susceptivity to eATP signals. The purinoceptor P2Y2, which proved to be overexpressed in patient cells, was identified as a pivotal receptor responsible for the enhanced ATP-induced or UTP-induced Ca(+) increase in affected myoblasts. Moreover, P2Y2 stimulation in LDMDR3 muscle cells induced chemotaxis of immune cells and release of interleukin-8. In conclusion, a higher eATP concentration and sensitivity in primary human muscle cells carrying different α-SG or γ-SG loss-of-function mutations indicate that eATP/P2Y2 is an enhanced signaling axis in cells from patients with α-/γ-sarcoglycanopathy. Understanding the basis of the innate immune-mediated damage associated with the dystrophic process may be critical in overcoming the immunologic hurdles associated with emerging gene therapies for these disorders.
Keywords:	Sarcoglycanopathies, Calcium, Purinergic Receptor, ATP, Patient-Derived Primary Myoblasts
Source:	Laboratory Investigation
ISSN:	0023-6837
Publisher:	Elsevier
Volume:	103
Number:	3
Page Range:	100037
Date:	March 2023
Official Publication:	https://doi.org/10.1016/j.labinv.2022.100037
PubMed:	View item in PubMed

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