Expression of the dermatomyositis autoantigen transcription intermediary factor 1γ in regenerating muscle.

OBJECTIVE: Autoantibodies against transcription intermediary factor 1γ (TIF1γ) are found in many patients with dermatomyositis (DM). Although TIF1γ is known to play a role in the differentiation of other tissues, its functional role in muscle regeneration has not been elucidated. This study was undertaken to explore the regulation and functional role of this protein during muscle differentiation and regeneration.

METHODS: TIF1γ expression was analyzed in human muscle biopsy specimens using immunofluorescence microscopy. Immunofluorescence microscopy and immunoblotting analyses were used to study TIF1γ expression in a mouse model of muscle injury and repair. The effect of premature TIF1γ silencing on muscle differentiation was studied in cultured mouse myoblasts.

RESULTS: In muscle biopsy specimens from DM patients, TIF1γ was expressed at low levels in the nuclei of histologically normal muscle cells but at high levels in the centralized nuclei of atrophic, perifascicular myofibers expressing markers of regeneration. TIF1γ levels were also increased in regenerating myonuclei following muscle injury in mice. Premature silencing of TIF1γ in vitro using small interfering RNA did not accelerate the expression of myogenin, a transcription factor that plays a central role in regulating relatively early stages of muscle differentiation. However, premature silencing of TIF1γ did accelerate myotube fusion and the expression of myosin heavy chain (MyHC), a later marker of muscle differentiation.

CONCLUSION: The DM autoantigen TIF1γ is markedly up-regulated during muscle regeneration in human and mouse muscle cells. Premature silencing of this protein in cultured myoblasts accelerates MyHC expression and myoblast fusion. However, TIF1γ may function independently of, or downstream from, myogenin.