Meeting Synopsis: Advances in Skeletal Muscle Biology in Health and Disease (Gainesville, Florida, February 22nd to 24th 2012) – Day 2: “Muscle Diseases and Regeneration” and “Clinical/Translational Research”

Dr. Girgenrath discussed her data on MDC1A, which is a severe form of congenital muscular dystrophy characterized by hypotonia, muscle weakness, and premature death. MDC1A results from deficiency in the laminin alpha 2 chain of laminin-211, an extracellular matrix protein mainly found in skeletal muscle and Schwann cells. Defects in laminin-211 cause major disruption of structural stability and signal transduction that leads to apoptosis, failed regeneration, and chronic inflammation. An emerging idea in the study of multiple diseases is that different pathological processes are intimately connected and can even amplify one another; this theory may apply to MDC1A. Dr. Girgenrath presented data showing that while targeting regeneration or apoptotic processes alone result in measurable improvement in the pathology of MDC1A/DyW mice, a combinatorial therapeutic approach that targets both results in marked improvement in pathology with larger, more uniform myofiber size as well as improved regeneration and reduced fibrosis. Dr. Girgenrath’s results suggest that dual therapy has promising potential as an effective treatment for MDC1A. Dr. Clemens showed her findings on NF-kappaB signaling in Duchenne muscular dystrophy (DMD). The chronic activation of NF-kappaB in dystrophic muscle leads to (1) infiltration of macrophages, (2) up-regulation of the ubiquitin-proteasome system, and (3) down-regulation of the helix-loophelix muscle regulatory factor, MyoD. Dr. Clemens has characterized the role of A20 (TNFAIP3), a critical negative regulator of NF-kappaB, in muscle regeneration. A20 is highly expressed in regenerating muscle fibers and knock down of A20 impairs muscle differentiation in vitro, suggesting that A20 expression is critically important region of PCG-1beta. Lastly, Dr. Guttridge revealed that activation of alternative signaling during myogenesis is under the control of mTOR and that mTOR regulation of PCG1beta occurs through NF-kappaB. Dr. Kumar described his findings showing that the expression and activity of various matrix metalloproteinases (MMPs) are dysregulated in skeletal muscle of dystrophin-deficient mdx mice. Treatment of mdx mice with Batimastat, a MMP inhibitory peptide, improved pathology and muscle contractile functions. Moreover, Dr. Kumar presented findings implicating MMP-9 as one of the most important MMPs involved in myofiber hypertrophy and necrosis, inflammation, and fibrosis in dystrophic muscle of mdx mice. Further, he also noted that increased levels of MMP-9 cause cardiomyopathy in 1-year-old mdx mice. Dr. Geisbrecht presented work on the signaling and cell adhesive events that underlie defects in the formation and/or maintenance of the myotendinous junction (MTJ), which result in progressive myopathies in vertebrate models and humans. Dr. Giesbrecht’s laboratory uses the fruit fly, Drosophila melanogaster as a model to identify and characterize new genes required for proper MTJ formation. Her group identified Moleskin (Msk) as the vertebrate ortholog of Importin-7. Loss of Msk function results in muscles that detach after muscle contraction begins. The canonical role of Importin-7/Msk is in nuclear import. However, in embryonic MTJ formation, Msk protein localizes to the sites of muscle-tendon attachment and is required for muscle to tendon signaling through the epidermal growth factor receptor signaling pathway to mediate stable formation of the MTJ. Future studies in the Geisbrecht laboratory will focus on Mskinteracting proteins to further define how proteins are shuttled and retained at the MTJ. Day 2 of the “Advances in Skeletal Muscle Biology in Health and Disease” conference consisted of 14 speakers across two sessions – “Muscle diseases and regeneration” and “Clinical/translational research.” The synopsis below outlines some of the main findings and future directions presented in these two sessions.