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

Catherine Koch (1) , Suzie Buono (1) , Alexia Menuet (2, 1) , Anne Robé (1) , Sarah Djeddi (2) , Christine Kretz (2) , Raquel Gomez Oca (2, 1) , Marion Depla (1) , Arnaud Monseur , Leen Thielemans (1) , Laurent Servais (3, 4, 5) , Jocelyn Laporte (2) , Belinda Cowling (1)

1 Dynacure
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
3 Institut de Myologie
4 CHU Trousseau [APHP]
5 Université de Liège

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 biomarker that may be used to monitor disease state in XL-CNM mice and patients and supports monitoring circulating myostatin during clinical trials for myotubular myopathy.

Mots clés: GDF8; MSTN; antisense oligonucleotides; biomarker; centronuclear myopathies; dynamin; myotubular myopathy; therapy

Domaines: Médecine humaine et pathologie

Catherine Koch, Suzie Buono, Alexia Menuet, Anne Robé, Sarah Djeddi, et al.. Myostatin: a Circulating Biomarker Correlating with Disease in Myotubular Myopathy Mice and Patients. Molecular Therapy - Methods and Clinical Development, 2020, 17, pp.1178-1189. ⟨10.1016/j.omtm.2020.04.022⟩. ⟨hal-03668015⟩