The long term goals of this research proposal are to evaluate the efficacy of myostatin inhibition as a treatment for myotubularin deficiency, which is responsible for X-linked myotubular myopathy (XLMTM) in human children. Children with XLMTM have severe weakness at an early age, and display small muscle fibers on muscle biopsy. While the function of myotubularin remains unclear, two murine models of myotubularin deficiency, the Mtm144 and Mtm1R69C models, have been developed to study this disease. We hypothesize that treatment strategies that increase muscle fiber size will cause symptomatic improvement in myotubularin deficient animals. One strategy to promote myofiber hypertrophy is through the inhibition of myostatin. Myostatin is a negative regulator of muscle growth, which can be knocked out or inhibited genetically or pharmacologically to produce mice with very large muscles and increased muscle strength. This proposal involves the use of a myostatin inhibitor called RAP-031 in the treatment of both strains of myotubularin- deficient mice, with subsequent studies designed to identify the mechanisms by which hypertrophy occurs or is limited in these animals. We will treat myotubularin deficient mice with RAP-031 and evaluate disease progression behaviorally, physiologically, and pathologically. Preliminary studies have shown that treatment of the more severe, Mtm144 mice causes an transient increase in weight, forelimb grip strength, and lifespan. Gene expression assays, microarrays, and Western blots will then be used to determine the activation of pathways involved in myofiber hypertrophy in treated and untreated mice, which can then be compared to the processes activated with RAP-031 in wild type animals. Using this information, further optimization of RAP- 031 treatment in myotubularin deficient animals will be attempted by combining it with other agents that promote myofiber hypertrophy. Based on our mechanistic studies and the results of multi-agent therapy in vitro, we will choose the two most promising combination therapies and test their efficacy in our myotubularin deficient mice. Success in this project would identify the optimal treatment regimen for patients with XLMTM using this therapeutic strategy, and provide the first treatment for this disease. Throughout my training, I have been fortunate enough to be mentored by exceptional scientists and physicians, which has culminated in my desire to pursue a career that incorporates what I have learned as a scientist and neuropathologist. My graduate work in the field of peripheral neuropathy, my current studies in congenital myopathy, and the loss of a childhood friend to muscular dystrophy have all contributed to my intense interest in developing novel treatment strategies for neuromuscular disease. My current full-time research position in the Beggs Lab at Children's Hospital Boston offers the ideal opportunity to pursue these goals, due to the collaborative environment, superb mentorship, and excellent technical resources that are available to me. Now that I have completed my clinical training, the funding provided by this K08 award would allow me to continue pursuing research as my major career focus as I continue to develop into an independent investigator, and the project described in this proposal provides a superb opportunity to pursue a new strategy for the treatment of congenital muscle disease.

Public Health Relevance

This proposal focuses on assessing a novel therapeutic strategy as a treatment for children with XLMTM. Patients with XLMTM have no current therapeutic options, and the relationship between this disease and small myofibers provides a justification for the use of myostatin inhibitors as therapeutic agents. Additionally, because the therapeutic strategy here is unrelated to the genetic defect in myotubularin deficient mice, the treatments proposed in these studies could also be effective in other patients with myopathic disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Boyce, Amanda T
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Medical College of Wisconsin
Schools of Medicine
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Tinklenberg, Jennifer A; Siebers, Emily M; Beatka, Margaret J et al. (2018) Myostatin inhibition using mRK35 produces skeletal muscle growth and tubular aggregate formation in wild type and TgACTA1D286G nemaline myopathy mice. Hum Mol Genet 27:638-648
Tinklenberg, Jennifer; Beatka, Margaret; Bain, James L W et al. (2018) Use Of Ankle Immobilization In Evaluating Treatments To Promote Longitudinal Muscle Growth In Mice. Muscle Nerve 58:718-725
Mack, David L; Poulard, Karine; Goddard, Melissa A et al. (2017) Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs. Mol Ther 25:839-854
Elverman, Matthew; Goddard, Melissa A; Mack, David et al. (2017) Long-term effects of systemic gene therapy in a canine model of myotubular myopathy. Muscle Nerve 56:943-953
Wu, Wei; Chordia, Mahendra D; Hart, Barry P et al. (2017) Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation. Bioorg Med Chem 25:1004-1013
Tinklenberg, Jennifer; Meng, Hui; Yang, Lin et al. (2016) Treatment with ActRIIB-mFc Produces Myofiber Growth and Improves Lifespan in the Acta1 H40Y Murine Model of Nemaline Myopathy. Am J Pathol 186:1568-81
Dastgir, Jahannaz; Rutkowski, Anne; Alvarez, Rachel et al. (2016) Common Data Elements for Muscle Biopsy Reporting. Arch Pathol Lab Med 140:51-65
Lawlor, Michael W; Beggs, Alan H; Buj-Bello, Ana et al. (2016) Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review With Cross-Species Comparisons. J Neuropathol Exp Neurol 75:102-10
Goddard, Melissa A; Mack, David L; Czerniecki, Stefan M et al. (2015) Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy. Ann Transl Med 3:262
Li, Frank; Buck, Danielle; De Winter, Josine et al. (2015) Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy. Hum Mol Genet 24:5219-33

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