Myostatin: a Circulating Biomarker Correlating with Disease in Myotubular Myopathy Mice and Patients

Molecular Therapy. Methods & Clinical Development
Catherine KochBelinda S Cowling

Abstract

Myotubular myopathy, also called X-linked centronuclear myopathy (XL-CNM), is a severe congenital disease targeted for therapeutic trials. To date, biomarkers to monitor disease progression and therapy efficacy are lacking. The Mtm1-/y mouse is a faithful model for XL-CNM, due to myotubularin 1 (MTM1) loss-of-function mutations. Using both an unbiased approach (RNA sequencing [RNA-seq]) and a directed approach (qRT-PCR and protein level), we identified decreased Mstn levels in Mtm1-/y muscle, leading to low levels of myostatin in muscle and plasma. Myostatin (Mstn or growth differentiation factor 8 [Gdf8]) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing Dnm2 by genetic cross with Dnm2+/- mice or by antisense oligonucleotides blocked or postponed disease progression and resulted in an increase in circulating myostatin. In addition, plasma myostatin levels inversely correlated with disease severity and with Dnm2 mRNA levels in muscles. Altered Mstn levels were associated with a generalized disruption of the myostatin pathway. Importantly, in two different forms of CNMs we identified reduced circulating myostatin levels in plasma from patients. This provides evidence of a blood-based ...Continue Reading

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Citations

Sep 11, 2020·Journal of Clinical Medicine·Laura Le GallJulie Dumonceaux
May 4, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sarah DjeddiJocelyn Laporte
Nov 19, 2021·Frontiers in Pharmacology·Theodora MarkatiLaurent Servais

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Methods Mentioned

BETA
biopsy
biopsies
antisense oligonucleotides
Antisense Oligonucleotide
PCR
protein Assay
electrophoresis

Clinical Trials Mentioned

NCT02310763
NCT02515669
NCT04033159
NCT03199469
NCT02057705
NCT03351270

Software Mentioned

Thermo Fisher cloud
Dynacure
FIJI
ImageJ

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