Functional and biochemical characterization of skeletal muscles of FRG1 over-expressing mice, transgenic mice, model of FSHD.

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary neuromuscular disorder characterized by progressive weakness and atrophy of the facial, shoulder, abdominal and pelvic girdle muscles. Evidence indicates the over-expression of genes mapped at distal long arm of chromosome 4 (4q35) as responsible for FSHD. Transgenic mice over-expressing FRG1 (FSHD Region Gene 1) at low, medium and high level were utilized to confirm this hypothesis. Indeed FRG1 transgenics develop a progressive muscular dystrophy whose degree of severity correlates with the level of expression of the transgene. Contractile properties of soleus, extensor digitorum longus and biceps muscles were studied in vitro at 30 °C. Calcium-sensitivity and specific tension of single fibres from soleus, vastus lateralis (VL) and biceps muscles were also analyzed. Functional properties were correlated to the expression of myosin heavy chains (MyHC), troponin C (TnC) and troponin T (TnT) isoforms. All muscles showed a progressive loss of twitch and tetanic tensions, confirmed by the lower specific tension recorded in single fibres. The pCa-tension relationship of VL and biceps fibres was significantly shifted to the right, particularly in mice expressing FRG1 at the highest level. SDS-PAGE and WB analyses of dystrophic muscles show a general shift toward a slow phenotype of both MyHC and TnC isoforms and an altered expression of fast TnT isoform.