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Abstract Details

The Role of Transcriptional Intermediary Factor 1-gamma (TIF1?), a Dermatomyositis Associated Autoantigen, in Muscle Fiber Differentiation and Regeneration
Muscle Disease/Neuromuscular Junction
P07 - (-)
047
BACKGROUND: Dermatomyositis (DM) is associated with muscle weakness and perifascicular atrophy on muscle biopsy. In patients with DM, specific autoantibodies (e.g., anti-Mi-2, -TIf1?, and -NXP2) are associated with unique clinical phenotypes. We have previously shown that the DM autoantigen Mi-2 is over-expressed in regenerating muscle fibers in DM and may restrain muscle differentiation. The expression of other DM autoantigens and their roles in muscle physiology is not understood.
DESIGN/METHODS: To study the expression of the DM autoantigen TIF1? during muscle regeneration in vivo, we used the cardiotoxin (CTX) model of muscle injury and repair. Mouse tibialis anterior muscles were collected at several time-points following CTX injection at several time-points and protein lysates were prepared. We defined the expression of TIF1? during muscle regeneration by quantitative immunoblotting. To study the expression of TIF1? as myoblasts differentiate into myotubes in vitro, we used cultured human skeletal muscle myoblasts (HSMMs) which can be induced to form myosin heavy chain (MyHC)-expressing myotubes. We also transiently transfected HSMMs to assess the effect of TIF1? over-expression on myoblast differentiation. Quantitative immunoblotting was employed to define TIF1?, myogenin, and MyHC expression levels.
RESULTS: TIF1? expression is low in normal mouse muscle, increases during muscle regeneration, and returns to baseline levels several weeks after muscle injury. In vitro, TIF1? is expressed at high levels in proliferating myoblasts and declines as they differentiate into MyHC-expressing myotubes. Transient over-expression of TIF1? in differentiating HSMMs disrupts myoblast differentiation and delays expression of MyHC and myogenin.
CONCLUSIONS: TIF1? is expressed at high levels in myoblasts relative to differentiated myofibers. Over-expression of TIF1? appears to restrain myoblast differentiation in vitro. The mechanism(s) of these effects remain to be elucidated.
Authors/Disclosures
Payam Mohassel, MD (Johns Hopkins University)
PRESENTER 		Dr. Mohassel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leal Therapeutics LLC. Dr. Mohassel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Mohassel has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Carr Maloney PC. Dr. Mohassel has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for SARNO DA COSTA D'ANIELLO MACERI WEBB ATTORNEYS AT LAW. The institution of Dr. Mohassel has received research support from NIH-- K22. The institution of Dr. Mohassel has received research support from DoD. The institution of Dr. Mohassel has received research support from Million Dollar Bike Ride UPenn. The institution of Dr. Mohassel has received research support from NIH-- R01. The institution of Dr. Mohassel has received research support from Packard Center for ALS Research. The institution of Dr. Mohassel has received research support from Live Like Lou Foundation. The institution of Dr. Mohassel has received research support from Maryland Stem Cell Research Fund. Dr. Mohassel has received personal compensation in the range of $0-$499 for serving as a CME Honorarium as Writer with MedLink Neurology. Dr. Mohassel has a non-compensated relationship as a Scientific Advisory Board Member with RYR1 Foundation that is relevant to AAN interests or activities. Dr. Mohassel has a non-compensated relationship as a Editorial Board member with Neuromuscular Disorders (Journal) that is relevant to AAN interests or activities. Dr. Mohassel has a non-compensated relationship as a Editorial Board member with Journal of Neuromuscular Diseases that is relevant to AAN interests or activities.
No disclosure on file
Andrew Mammen, MD, PhD (NIH) Dr. Mammen has received research support from National Institutes of Health. The institution of an immediate family member of Dr. Mammen has received research support from National Institutes of Health. Dr. Mammen has received intellectual property interests from a discovery or technology relating to health care.
No disclosure on file