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Myostatin: a Circulating Biomarker Correlating with Disease in Myotubular Myopathy Mice and Patients
Catherine Koch1, Suzie Buono1, Alexia Menuet1,2,3,4,5
1Dynacure, Illkirch, France.
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 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.
Insights
Circulating myostatin levels are reduced in X-linked myotubular myopathy (XL-CNM) patients and mice. This finding identifies myostatin as a potential biomarker for monitoring disease progression and therapeutic efficacy in XL-CNM clinical trials.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- X-linked myotubular myopathy (XL-CNM) is a severe congenital muscle disease lacking biomarkers for monitoring progression and treatment efficacy.
- The Mtm1 knockout mouse model recapitulates XL-CNM, offering a platform for biomarker discovery.
Purpose of the Study:
- To identify reliable biomarkers for assessing disease state and therapeutic response in XL-CNM.
- To investigate the role of myostatin in XL-CNM pathogenesis and its potential as a circulating biomarker.
Main Methods:
- RNA sequencing (RNA-seq), qRT-PCR, and protein analysis were employed to identify molecular changes in Mtm1 knockout mice.
- Genetic modification (Dnm2+/- cross) and antisense oligonucleotide treatment were used to modulate disease progression.
- Plasma and muscle samples from XL-CNM mice and patients were analyzed for myostatin levels.
Main Results:
- Decreased myostatin (Mstn) levels were observed in the muscle and plasma of Mtm1 knockout mice.
- Therapeutic interventions targeting Dnm2 delayed disease progression and increased circulating myostatin.
- Plasma myostatin levels inversely correlated with disease severity and Dnm2 mRNA levels.
- Reduced circulating myostatin was consistently found in patients with two forms of centronuclear myopathies (CNMs).
Conclusions:
- Myostatin is a potential blood-based biomarker for monitoring disease progression in XL-CNM.
- Circulating myostatin levels can inform therapeutic efficacy during clinical trials for myotubular myopathy.
- Altered myostatin pathway signaling is implicated in the pathophysiology of XL-CNM.
