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Mineralocorticoid and Glucocorticoid Signaling Differently Affect Skeletal Muscle Inflammation in Muscular Dystrophy.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Mineralocorticoid and Glucocorticoid Signaling Differently Affect Skeletal Muscle Inflammation in Muscular Dystrophy./
作者:	Howard, Zachary M.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	218 p.
附註:	Source: Dissertations Abstracts International, Volume: 84-01, Section: B.
Contained By:	Dissertations Abstracts International84-01B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29310725
ISBN:	9798834018933

Mineralocorticoid and Glucocorticoid Signaling Differently Affect Skeletal Muscle Inflammation in Muscular Dystrophy.
Howard, Zachary M.

Mineralocorticoid and Glucocorticoid Signaling Differently Affect Skeletal Muscle Inflammation in Muscular Dystrophy. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 218 p.

Source: Dissertations Abstracts International, Volume: 84-01, Section: B.

Thesis (Ph.D.)--The Ohio State University, 2021.

This item must not be sold to any third party vendors.

Duchenne muscular dystrophy (DMD) is an inherited degenerative disease affecting all striated muscles with limited treatment options. Long-term glucocorticoid therapy to activate glucocorticoid receptor (GR) signaling is the standard of care for DMD that moderately improves skeletal muscle strength, but has severe side effects. Potential alternatives to glucocorticoid treatment include mineralocorticoid receptor antagonists (MRA), such as spironolactone or eplerenone that demonstrate efficacy on dystrophic skeletal and cardiac muscle function and pathology. Previously, we determined that the mineralocorticoid receptor (MR) in muscle fibers is involved in chronic (dystrophic) and acute skeletal muscle injury. Myofiber MR ablation reduces fibrosis and improves skeletal muscle force in dystrophic mice, recapitulating some of the benefits from MRA treatment. In this thesis, we targeted myeloid MR signaling in dystrophic and acutely injured mouse skeletal muscle and compared the effects of glucocorticoids and MRAs in dystrophic mice.We first optimized novel skeletal isolation protocols and utilized the methodology to compare inflammation between two dystrophic mouse models, dystrophin-deficient mdx and dystrophin-deficient/utrophin-haploinsufficient het mice. Het mouse skeletal muscle is more inflamed at the protein, transcript, and cellular level, particularly by monocytes, neutrophils, and M1 macrophages. Additionally, het quadriceps contains more F4/80Hi macrophages than het diaphragms, suggesting skeletal muscle-specific differences in immune-mediated regeneration during peak necrosis. Het quadriceps F4/80Hi macrophages with membrane CCR2 also expresses more CD206, pro-inflammatory, and pro-fibrotic transcripts, indicating nuances to the F4/80Hi macrophage population.Conditional knockout of myeloid MR (MRcko) in mdx and wild-type mice affects both chronic and acute muscle injuries. Inflammatory signaling, fibrosis, and immune cell populations are affected in MRcko-mdx quadriceps and diaphragms, which collectively appears to exacerbate pathology. Negative effects on healing are also observed in acutely injured MRcko-WT tibialis anterior (TA) muscles, accumulating more myofiber degeneration, decreasing the proportion of M2 macrophages, and upregulating myofiber aldosterone synthase (CYP11B2) to compensate for the loss of myeloid MR signaling.Spironolactone, a MRA, and prednisolone, a glucocorticoid metabolite, were also administered to mdx mice to compare the effects of these commonly prescribed drugs on spleen, blood, and skeletal muscle inflammation. Spironolactone and prednisolone both reduce inflammatory signaling in mdx quadriceps, but prednisolone substantially increases chemokine and cytokine signaling mdx diaphragms relative to vehicle controls. Both drugs elevate percentages of neutrophils in mdx spleens and blood, however, prednisolone also preferentially increased monocytes. Spironolactone does not significantly affect the distribution of leukocytes in mdx quadriceps and diaphragms. Prednisolone affects more myeloid populations in mdx quadriceps than spironolactone, including increasing F4/80Hi macrophages in mdx quadriceps and increasing the percentage of neutrophils in mdx diaphragms.Together, these studies indicate that pharmacological versus genetic inhibition of myeloid MR produces conflicting outcomes in dystrophic mouse skeletal muscle. Acute muscle injury also suggests an important role for myeloid MR in repair, which is supported by our previous studies. In addition, care should be exercised when prescribing glucocorticoids for DMD patients, since potent immunosuppression during peak diaphragm necrosis appears to cause more inflammatory signaling.

ISBN: 9798834018933Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Mineralocorticoid signaling

Mineralocorticoid and Glucocorticoid Signaling Differently Affect Skeletal Muscle Inflammation in Muscular Dystrophy.
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