Résumé :
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Background: Hereditary inclusion body myopathy type 2 (hIBM) is a rare autosomal-recessive disorder due to mutations in the UDP-N-Acetylglucosamine2-Epimerase/NAcetylmannosamine kinase [GNE]. The model of the Gne-/-hGNED176VL-Tg mouse resembles the phenotype in humans and shows histopathological changes typical for hIBM from week 40 onward. Homozygous GNE deficiency in our mouse model (C57Bl/6 GNE-/-) was shown to be letal at embryonic day 8.5. The content of sialic acid in various organs was on average 20% lower in C57Bl/6 GNE+/- compared to C57Bl/6 wildtype. An about 20% lower performance in the treadmill exercise in C57Bl/6 GNE+/- compared to C57Bl/6 wildtype prompted us to analyse the heterozygous C57Bl/6 GNE+/- mouse model. Materials/methods: We analysed animals after 5 months (n=6 C57Bl/6 GNE+/-, n=6 C57Bl/6) and after 18 months (n=12 C57Bl/6 GNE+/-, n=8 C57Bl/6) for total body weight, weight of gastrocnemius, anterior tibial, and quadriceps femoris muscles, serum creatine kinase (CK) levels, histopathological changes by light and electron microscopy, as well as total and membrane bound content of sialic acid.Results:Total body and muscle weight and muscle fibre diameter did not differ neither between C57Bl/6 GNE +/- and C57Bl/6 nor over time. There was a mild increase in serum CK levels over time but no difference between both groups. The number of internalized nuclei increased over time but was not different between the two groups (5 months: C57Bl/6 GNE+/- = 0.2+0.1, C57Bl/6 = 0.3+0.1, C57Bl/6 GNE+/- 5.5+1.5, C57Bl/6 = 5.2+2.0). After 18 months both C57Bl/6 GNE+/- and C57Bl/6 wildtype showed a similar extent in empty rimmed vacuoles in hematoxilin and eosin and modified Gomori trichrome staining ranging from 0-50%, more pronounced in quadriceps femoris and gastrocnemius than tibial muscle. However, these vacuoles did not stain positive for TDP43, acid phosphatase, and caveolin 3. The content in total sialic acid did not seem to decrease over time in heterozygous and wildtype animals. Conclusions: Changes in the content of sialic acid in a heterozygous GNE knock out mouse model seem to be well compensated. This is in line with human heterozygous carriers of GNE mutations. In contrast to the dramatic effects of homozygous GNE knock out models the C57Bl/6 GNE+/- did not develop any specific phenotype. The vacuoles in both heterozygous and wildtype mice might rather reflect ageing processes in skeletal muscle.
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