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Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy
Michael W Lawlor1, Dustin Armstrong, Marissa G Viola
1Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Abstract:
No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1δ4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency. Contractile function of intact extensor digitorum longus (EDL) and soleus muscles from Mtm1δ4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1δ4 muscle were largely preserved, indicating that weakness was largely due to impaired excitation contraction coupling. Mtm1 p.R69C mice, which produce small amounts of myotubularin, showed impaired contractile function only in EDL muscles. Short-term replacement of myotubularin with a prototypical targeted protein replacement agent (3E10Fv-MTM1) in Mtm1δ4 mice improved contractile function and muscle pathology. These promising findings suggest that even low levels of myotubularin protein replacement can improve the muscle weakness and reverse the pathology that characterizes XLMTM.
Insights
X-linked myotubular myopathy (XLMTM) treatment is lacking. Protein replacement therapy with 3E10Fv-MTM1 in mouse models showed improved muscle function and pathology, suggesting potential for XLMTM treatment.
Area of Science:
- Biochemistry
- Genetics
- Neuromuscular Disorders
Background:
- X-linked myotubular myopathy (XLMTM) is a severe congenital muscle disease.
- XLMTM results from myotubularin deficiency, with no current effective treatments.
- Mouse models (Mtm1δ4 and Mtm1 p.R69C) replicate XLMTM severity based on myotubularin levels.
Purpose of the Study:
- To investigate the efficacy of myotubularin protein replacement in XLMTM mouse models.
- To assess the impact of myotubularin restoration on muscle contractile function and pathology.
Main Methods:
- Evaluated contractile function of extensor digitorum longus (EDL) and soleus muscles in Mtm1δ4 and Mtm1 p.R69C mice.
- Utilized chemically skinned single muscle fiber preparations to differentiate between excitation-contraction coupling and intrinsic fiber deficits.
- Administered a targeted protein replacement agent (3E10Fv-MTM1) to Mtm1δ4 mice for short-term myotubularin replacement.
Main Results:
- Mtm1δ4 mice (no myotubularin) exhibited severely impaired muscle contractile function, primarily due to excitation-contraction coupling defects.
- Mtm1 p.R69C mice (low myotubularin) showed impaired contractile function specifically in EDL muscles.
- Short-term 3E10Fv-MTM1 treatment in Mtm1δ4 mice significantly improved muscle contractile function and reversed pathological features.
Conclusions:
- Muscle weakness in XLMTM is largely attributed to impaired excitation-contraction coupling.
- Even minimal myotubularin protein replacement can substantially improve muscle function and pathology in XLMTM.
- Targeted protein replacement therapy represents a promising therapeutic strategy for X-linked myotubular myopathy.
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