Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

Anabel S. De la Garza-Rodea; Steven A. Moore; Jesus Zamora-Pineda; Eric P. Hoffman; Karishma Mistry; Ashok Kumar; Jonathan B. Strober; Piming Zhao; Jung H. Suh; Julie D. Saba

doi:10.3390/ijms23147579

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Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

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Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

Anabel S. De la Garza-Rodea, Steven A. Moore, Jesus Zamora-Pineda, Eric P. Hoffman, Karishma Mistry, Ashok Kumar, Jonathan B. Strober, Piming Zhao, Jung H. Suh and Julie D. Saba

International journal of molecular sciences, Vol.23(7579), p.7579

07/01/2022

DOI: 10.3390/ijms23147579

PMCID: PMC9316262

PMID: 35886926

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Abstract

Duchenne muscular dystrophy (DMD) is a congenital myopathy caused by mutations in the dystrophin gene. DMD pathology is marked by myositis, muscle fiber degeneration, and eventual muscle replacement by fibrosis and adipose tissue. Satellite cells (SC) are muscle stem cells critical for muscle regeneration. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes SC proliferation, regulates lymphocyte trafficking, and is irreversibly degraded by sphingosine phosphate lyase (SPL). Here, we show that SPL is virtually absent in normal human and murine skeletal muscle but highly expressed in inflammatory infiltrates and degenerating fibers of dystrophic DMD muscle. In mdx mice that model DMD, high SPL expression is correlated with dysregulated S1P metabolism. Perinatal delivery of the SPL inhibitor LX2931 to mdx mice augmented muscle S1P and SC numbers, reduced leukocytes in peripheral blood and skeletal muscle, and attenuated muscle inflammation and degeneration. The effect on SC was also observed in SCID/mdx mice that lack mature T and B lymphocytes. Transcriptional profiling in the skeletal muscles of LX2931-treated vs. control mdx mice demonstrated changes in innate and adaptive immune functions, plasma membrane interactions with the extracellular matrix (ECM), and axon guidance, a known function of SC. Our cumulative findings suggest that by raising muscle S1P and simultaneously disrupting the chemotactic gradient required for lymphocyte egress, SPL inhibition exerts a combination of muscle-intrinsic and systemic effects that are beneficial in the context of muscular dystrophy.

Duchenne muscular dystrophy

mdx

satellite cells

sphingosine phosphate lyase

sphingosine-1-phosphate

Details

Title: Subtitle: Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice
Creators: Anabel S. De la Garza-Rodea - University of California, San Francisco
Steven A. Moore - University of Iowa
Jesus Zamora-Pineda - University of California, San Francisco
Eric P. Hoffman - Binghamton University
Karishma Mistry - University of California, San Francisco
Ashok Kumar - University of California, San Francisco
Jonathan B. Strober - UCSF Benioff Children's Hospital
Piming Zhao - University of California, San Francisco
Jung H. Suh - University of California, San Francisco
Julie D. Saba - University of California, San Francisco
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.23(7579), p.7579
DOI: 10.3390/ijms23147579
PMID: 35886926
PMCID: PMC9316262
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Publisher: MDPI AG
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: GM66954, P50NS053672; DOI: 10.13039/100005202, name: Muscular Dystrophy Association, award: MDA217712; DOI: 10.13039/100007557, name: California Institute of Regenerative Medicine, award: TG2-01164
Language: English
Date published: 07/01/2022
Academic Unit: Pathology
Record Identifier: 9984276446202771

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