Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit

Molecular Therapy : the Journal of the American Society of Gene Therapy
Sen Chandra SreetamaJyoti K Jaiswal

Abstract

Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental therapeutic approach for LGMD2B is to protect damage or improve repair of myofiber sarcolemma. Here, we compared the effects of prednisolone and vamorolone (a dissociative steroid; VBP15) on dysferlin-deficient myofiber repair. Vamorolone, but not prednisolone, stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) myofibers injured by focal sarcolemmal damage, eccentric contraction-induced injury or injury due to spontaneous in vivo activity. Vamorolone decreased sarcolemmal lipid mobility, increased muscle strength, and decreased late-stage myofiber loss due to adipogenic infiltration. In contrast, the conventional glucocorticoid prednisolone failed to stabilize dysferlin deficient muscle cell membrane or improve repair of dysferlinopathic patient myoblasts and mouse myofibers. Instead, prednisolone treatment increased muscle weakness and myofiber atrophy in B6A/J mice-findings...Continue Reading

Citations

Feb 12, 2019·Journal of Clinical Pharmacology·Panteleimon D MavroudisWilliam J Jusko
Jun 5, 2019·Nature Communications·Marshall W HogarthJyoti K Jaiswal
Nov 21, 2019·American Journal of Physiology. Cell Physiology·Thomas A KwiatkowskiNoah Weisleder
Aug 28, 2019·Neurology·Eric P HoffmanUNKNOWN Cooperative International Neuromuscular Research Group
Aug 26, 2019·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Jesse M DamskerKanneboyina Nagaraju
May 21, 2020·Journal of Clinical Pharmacology·Xiaonan LiWilliam J Jusko
Feb 13, 2019·Life Science Alliance·Christopher R HeierChristopher F Spurney
Aug 8, 2020·International Journal of Molecular Sciences·Adam J BittelYi-Wen Chen
Sep 29, 2020·Biochemical Society Transactions·Adam Horn, Jyoti K Jaiswal
Apr 10, 2020·PloS One·Brian J PaleoNoah Weisleder
Aug 23, 2020·Cells·Daniel C BittelJyoti K Jaiswal
Feb 19, 2020·Disease Models & Mechanisms·Jennifer Morgan, Terence Partridge
Aug 17, 2019·Biomaterials·Jason WangNenad Bursac
Jan 20, 2021·Cell Discovery·Catarina Dias, Jesper Nylandsted
Oct 27, 2020·Journal of Neuromuscular Diseases·Mattia QuattrocelliElizabeth M McNally
Apr 20, 2020·The American Journal of Pathology·Martin FlückChristian Gerber
Jun 11, 2021·The Protein Journal·Dimitra G GeorganopoulouChih-Kao Hu
Jun 19, 2021·Molecular Therapy. Methods & Clinical Development·Kyowon SeoJin-Hong Shin

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Methods Mentioned

BETA
fluorescence recovery after photobleaching
chemical modification

Clinical Trials Mentioned

NCT02760264
NCT02760277
NCT03038399
NCT03439670
NCT03558958

Software Mentioned

GraphPad Prism
CellSens
Slidebook

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