Limb-girdle muscular dystrophy type 2B causes HDL-C abnormalities in patients and statin-resistant muscle wasting in dysferlin-deficient mice.
Cholesterol
Dysferlin
Dyslipidemia
Simvastatin
Journal
Skeletal muscle
ISSN: 2044-5040
Titre abrégé: Skelet Muscle
Pays: England
ID NLM: 101561193
Informations de publication
Date de publication:
29 11 2022
29 11 2022
Historique:
received:
07
07
2022
accepted:
11
11
2022
entrez:
29
11
2022
pubmed:
30
11
2022
medline:
2
12
2022
Statut:
epublish
Résumé
Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage. Herein, lipoproteins and liver enzymes from LGMD2B patients and dysferlin-null (Dysf) mice were analyzed. Simvastatin, which exhibits anti-muscle wasting effects in mouse models of DMD and corrects aberrant expression of key markers of lipid metabolism and endogenous cholesterol synthesis, was tested in Dysf mice. Muscle damage and fibrosis were assessed by immunohistochemistry and cholesterol signalling pathways via Western blot. LGMD2B patients show reduced serum high-density lipoprotein cholesterol (HDL-C) levels compared to healthy controls and exhibit a greater prevalence of abnormal total cholesterol (CHOL)/HDL-C ratios despite an absence of liver dysfunction. While Dysf mice presented with reduced CHOL and associated HDL-C and LDL-C-associated fractions, simvastatin treatment did not prevent muscle wasting in quadriceps and triceps muscle groups or correct aberrant low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) protein expression. LGMD2B patients present with reduced serum concentrations of HDL-C, a major metabolic comorbidity, and as a result, statin therapy is unlikely to prevent muscle wasting in this population. We propose that like DMD, LGMD2B should be considered as a new type of genetic dyslipidemia.
Identifiants
pubmed: 36447272
doi: 10.1186/s13395-022-00308-6
pii: 10.1186/s13395-022-00308-6
pmc: PMC9706908
doi:
Substances chimiques
Dysferlin
0
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
Dystrophin
0
Cholesterol, HDL
0
Simvastatin
AGG2FN16EV
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
25Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
© 2022. The Author(s).
Références
Circulation. 2008 Nov 11;118(20):2047-56
pubmed: 18955664
Front Physiol. 2021 Jul 22;12:675322
pubmed: 34366880
Neurology. 2019 Sep 24;93(13):e1312-e1323
pubmed: 31451516
Lancet Neurol. 2018 Apr;17(4):347-361
pubmed: 29395990
Skelet Muscle. 2021 Sep 3;11(1):21
pubmed: 34479633
Anat Rec (Hoboken). 2020 Aug;303(8):2202-2212
pubmed: 31855314
J Endocrinol Invest. 2020 May;43(5):663-675
pubmed: 31786795
J Cell Biol. 1993 Aug;122(4):809-23
pubmed: 8349731
J Lipid Res. 2019 Aug;60(8):1350-1364
pubmed: 31203232
Nat Rev Mol Cell Biol. 2020 Apr;21(4):225-245
pubmed: 31848472
Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12864-9
pubmed: 26417069
Lancet Neurol. 2018 Mar;17(3):251-267
pubmed: 29395989
Am J Physiol Cell Physiol. 2012 Sep 1;303(5):C475-85
pubmed: 22700795
Eur J Neurol. 2021 Jun;28(6):2092-2102
pubmed: 33715265
Skelet Muscle. 2017 Sep 12;7(1):19
pubmed: 28899419
Lancet Neurol. 2018 May;17(5):445-455
pubmed: 29398641
J Lipid Res. 2007 Mar;48(3):646-55
pubmed: 17189607
Biochem Biophys Res Commun. 2020 Apr 2;524(2):510-515
pubmed: 32014257
J Physiol. 2006 Jul 1;574(Pt 1):63-71
pubmed: 16613876
Joint Bone Spine. 2020 Jan;87(1):37-42
pubmed: 30735805
J Lipid Res. 2018 Feb;59(2):261-272
pubmed: 29175948
Neurol Neuroimmunol Neuroinflamm. 2018 Dec 12;6(1):e523
pubmed: 30588482
Diabetes Metab Syndr. 2018 Apr - Jun;12(2):81-85
pubmed: 28869151
Muscle Nerve. 2020 Jan;61(1):26-35
pubmed: 31599456
Magn Reson Imaging. 2017 May;38:163-173
pubmed: 28069416
J Neuromuscul Dis. 2021;8(5):845-863
pubmed: 33044191
PLoS Med. 2020 Sep 21;17(9):e1003222
pubmed: 32956407
Physiol Rep. 2019 Mar;7(6):e14018
pubmed: 30912308
Biochem Biophys Res Commun. 2015 Oct 23;466(3):536-40
pubmed: 26381177
J Clin Lipidol. 2020 Jul - Aug;14(4):459-469.e0
pubmed: 32593511
J Cachexia Sarcopenia Muscle. 2021 Jun;12(3):677-693
pubmed: 34037326
Int J Biochem Cell Biol. 2016 Sep;78:10-21
pubmed: 27343428
Neurol Sci. 2019 May;40(5):1035-1040
pubmed: 30790082
Muscle Nerve. 2011 Feb;43(2):283-6
pubmed: 21254096
Nature. 2003 May 8;423(6936):168-72
pubmed: 12736685
Clin Neurol Neurosurg. 2020 Apr;191:105687
pubmed: 32004987
Biochim Biophys Acta. 2015 Aug;1853(8):1841-9
pubmed: 25913013
J Cachexia Sarcopenia Muscle. 2022 Feb;13(1):544-560
pubmed: 34927367
Arch Intern Med. 2012 Dec 10;172(22):1707-10
pubmed: 23147400
NMR Biomed. 2010 Jan;23(1):13-22
pubmed: 19787747
Lipids Health Dis. 2019 Jan 26;18(1):28
pubmed: 30684968
Dis Markers. 2015;2015:543282
pubmed: 26063958
Circulation. 2013 Nov 26;128(22):2364-71
pubmed: 24170386