Differential Dysferlin Expression in Human Fast and Slow Muscle: Clinical Correlation with LGMD-D2 Evolution (P6-8.003)

Abstract

<h3>Objective:</h3> To evaluate human dysferlin level in slow and fast human muscle and correlate its quantity with LGMD-D2 dystrophy evolution. <h3>Background:</h3> Dysferlinopathy is a common form of limb girdle muscular dystrophy (LGMD) presenting either as LGMDR2/2B or distal Miyoshi myopathy, that show different clinical course. They are caused by mutations in the DYSF gene encoding the protein dysferlin, a transmembrane sarcolemmal protein which has a role in the repair of sarcolemma. Dysferlin is also a T-tubule protein. Dysferlin expression in skeletal muscle fibre types has not been studied so far. <h3>Design/Methods:</h3> We investigated by Western Blotting human skeletal muscles, one proximal in the arm (biceps brachii) and the other distal in the leg (tibialis anterior), which are affected differently during the course of LGMDR2: with onset first in tibialis anterior (around the age of 20 years) and only late involvement the biceps brachii, around the age of 45 years. Muscle specimen were collected after a few hours either in control from sudden death or in muscle biopsies (male 60, 63 year/old; female 48, 52 year/old) of biceps brachii and tibialis anterior and in the 4 muscles analysed, Dysferlin/Myosin ratio was calculated. <h3>Results:</h3> Western blotting results from skeletal muscles showed that in arm the biceps brachii and in leg distal tibialis mucle contains a different amont of dysferlin protein. Dysferlin to myosin heavy chain ratio was higher in biceps brachii (2.26–2.36) than in tibialis anterior muscle (1.17–1.56). Our results show a higher “content” of dysferlin in fast skeletal muscle, i.e. biceps brachii, compared to slow, i.e. tibialis anterior, related to increased resistance to eccentric exercise and muscle fiber injury. <h3>Conclusions:</h3> We found a higher level of dysferlin in biceps brachii, which is involved later in LGMD-D2 disease course versus tibialis anterior muscle, that degenerates earlier, this difference might explain the different muscle involvement observed in LGMDR2/2B and Miyoshi myopathy. <b>Disclosure:</b> Dr. MEZNARIC has nothing to disclose. Dr. Angelini has nothing to disclose.