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Mechanisms of Muscle Wasting in DM1

Many Muscular Dystrophies, Yet Diverse Paths to Muscle Atrophy

By definition, the muscular dystrophies are diseases that cause progressive muscle atrophy and weakness. Often, as in myotonic dystrophy, other body systems are involved as well, but it is the atrophy and weakness that are the traditional hallmarks of the disease. Loss of skeletal muscle mass has been linked to variety of causes across the various types of muscular dystrophy—from the breakdown of the sarcomere and calcium-triggered proteolysis in mutations of the dystrophin-dystroglycan complex (e.g., dystrophinopathies and some forms of LGMD) to mutations in nuclear lamins, which disrupt intracellular signaling (e.g., EDMD) to mutations that alter sarcolemmal repair (e.g., dysferlinopathies). By contrast, the molecular mechanisms linking expanded repeat tracts to muscle atrophy in DM are largely unresolved.

Insights from a New Mouse Model

Dr. Ginny Morriss, an MDF fellow, and her mentor, Dr. Tom Cooper, and their colleagues at Baylor College of Medicine have developed a novel mouse model and used it to gain insights into the molecular mechanisms behind skeletal muscle wasting in DM1. Their findings suggest that disruption of specific cell signaling pathways may be an important contributor to muscle atrophy in the mouse model.

The Baylor research team developed a skeletal muscle-specific, tet-inducible mouse expressing 960 CUG repeats in the context of human DMPK exons 11-12 (CUG960 mouse). While the mice showed substantial skeletal muscle atrophy—reduced muscle weight and histologic abnormalities—and MBNL-containing nuclear foci, the splicopathy that normally characterizes DM1 was mild. Likewise, Celf1,GSK3β, or cyclin D3 levels did not show significant changes in induced CUG960 mice.

Induction of CUG960 induction in utero or at postnatal day 1 produced similar skeletal muscle outcomes. Muscle loss was also observed when CUG960 mice were induced at 6 weeks of age, but effects were less consistent across muscle groups. Additional assays failed to detect alterations in total protein synthesis levels as an underlying mechanism. Turning off CUG960 expression ten weeks after induction at postnatal day 1 reversed the skeletal muscle effects in some, but not the most severely affected, muscle groups.

DM1 Spliceopathy Does Not Fully Explain Muscle Wasting in DM1

Since the splicing defects in induced CUG960 mice were mild, the research team sought to understand other potential mechanisms for skeletal muscle atrophy. Reverse phase protein array analysis, an antibody-based assay to quantitatively assess large numbers of biologic samples for alterations in signaling pathways, identified substantial alterations in protein abundance—77 proteins up-regulated and 2 down-regulated. The protein assay findings correlated with other measures of muscle wasting on a sample-by-sample basis. Altered phosphorylation of some signaling pathway components was also noted.

Observed disruptions in signaling pathway components were interpreted as reflective of a deregulation of PDGFRβ receptor signaling and the PI3K/AKT pathways, along with prolonged activation of AMPKα signaling. The research team obtained similar results in analyses of DM1 patient muscle biopsy material, providing additional validation for the mouse model studies.

Overall, the alterations in cellular signaling support the concept that alterations in the balance of anabolic and catabolic pathways that normally maintain muscle mass, independent of MBNL-triggered splicing abnormalities, is an important contributor to muscle atrophy in DM1. Modeling of skeletal muscle atrophy in DM then must take into account mechanisms dependent and independent of reductions in free MBNL levels.

Reference:

Mechanisms of skeletal muscle wasting in a mouse model for myotonic dystrophy type 1.
Morriss GR, Rajapakshe K, Huang S, Coarfa C, Cooper TA.
Hum Mol Genet. 2018 May 16. doi: 10.1093/hmg/ddy192. [Epub ahead of print]

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