MR AND MICRO-CT OF MYOFIBRILLAR PATHOLOGY IN MOUSE MODEL OF LGMD1A

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. I have recently generated transgenic mice expressing the limb-girdle muscular dystrophy type 1A (LGMD1A) thr57ile myotilin mutation (TgT57I) specifically in skeletal muscle. The transgene includes the human myotilin cDNA and an N-terminal c-myc epitope tag. Three independent lines of TgT57I mice develop progressive myofibrillar pathology (fig. 1a, unpublished data). Sections of multiple muscles show an age-dependent increase in the size and number of dense myofibrillar plaques or aggregates. Ultrastructural analysis reveals rimmed vacuoles, Z-disc streaming, and large patches of myofibrillar disarray (fig. 1b, unpublished data) similar to those seen in human patients. Transgenic mice overexpressing the human wild-type myotilin cDNA develop no abnormal myopathology. To further characterize the TgT57I mice, we performed whole muscle physiology. The EDL muscle¿s mass is reduced by 33%, its cross-sectional area is reduced 30%, and its maximum specific force is reduced 23%. In contrast to the largely fast-twitch EDL muscle, TgT57I soleus muscle physiology remains normal; the soleus is also spared of any myopathology. Further histological analysis of muscle groups in TgT57I mice reveals that certain muscles such as quadriceps and triceps are heavily populated with myoaggregates while others such as tibialis anterior and diaphragm are spared. Similarly, in LGMD1A, there is tremendous variability in the degree of pathology between muscles detected by MRI and CT-scans. For example, scan of an LGMD1A hamstring shows specific involvement and assymetrical wasting of the semimembranosous (unpublished data). I wish to more thoroughly evaluate the pattern and symmetry of muscle wasting in the TgT57I mouse model by magnetic resoncance microscopy. Because male inbred mice develop a gross nonspecific tubular aggregate pathology, I propose to analyze a 12-month old female TgT57I mouse. MicroCT and MRM imaging will facilitate an unprecedentedly complete evaluation of muscle groups in a mouse model of muscle disease.