From T‐tubule to sarcolemma: damage‐induced dysferlin translocation in early myogenesis

Abstract

The dysferlin gene is mutated in limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, and distal anterior compartment myopathy. In mature skeletal muscle, dysferlin is located predominantly at the sarcolemma, where it plays a role in membrane fusion and repair. To investigate the role of dysferlin during early muscle differentiation, its localization was studied at high resolution in a muscle cell line. This demonstrated that dysferlin is not expressed at the plasmalemma of myotubes but mostly localizes to the T-tubule network. However, dysferlin translocated to the site of injury and toward the plasma membrane in a Ca2+-dependent fashion in response to a newly designed in vitro wounding assay. This reaction was specific to the full-length protein, as heterologously expressed deletion mutants of distinct C2 domains of dysferlin did not show this response. These results shed light on the dynamics of muscle membrane repair and are highly indicative of a specific role of dysferlin in this process in early myogenesis.

Affixin activates Rac1 via βPIX in C2C12 myoblast

“…Similarly, activated satellite cells form lamellipodia and migrate around the injured lesion during skeletal muscle regeneration [26]. Very recently, dysferlin reportedly localized in the T-tubule system of differentiating C2C12 cells and was recruited to the wounded site [27]. Dysferlin is known to have an important role in skeletal muscle wound healing [11].…”

Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy

“…It functions in excitation-contraction (EC) coupling by propagating the action potential from the plasma membrane into the muscle fiber, ultimately leading to Ca 2+ release from the sarcoplasmic reticulum (SR) and to muscle contraction. The T-tubule system is involved in the regulation of muscle fatigue, muscle differentiation, intracellular trafficking and plasma membrane repair (Al-Qusairi and Laporte, 2011;Engel and Franzini-Armstrong, 2004;Kerr et al, 2014;Klinge et al, 2007;Krolenko and Lucy, 2002;Lee et al, 2002). However, the molecular mechanisms required for biogenesis, maintenance and function of this cellular organelle are only partially understood (Al-Qusairi and Laporte, 2011;Engel and Franzini-Armstrong, 2004).…”

“…Mutations in genes coding for Bin1 and caveolin-3 each induce different muscle diseases (Bohm et al, 2014), with alterations in Ca 2+ homeostasis arising from Bin1 deficiency (Tjondrokoesoemo et al, 2011). Indirect observations have pointed to a function of dysferlin in T-tubule biogenesis (Al-Qusairi and Laporte, 2011;Demonbreun et al, 2013;Kerr et al, 2014Kerr et al, , 2013Klinge et al, 2010bKlinge et al, , 2007. Mutations in the DYSF gene lead to limb-girdle muscular dystrophy type 2B (LGMD2B) or Miyoshi myopathy (MM), characterized by progressive muscular weakness and wasting, which typically start in the second decade of life.…”

Non-invasive protein analysis in the first dysferlinopathy Croatian families

“…The main characteristic of this protein family is the presence of multiple C2 domains (ranging from four to seven, latter being the number present in dysferlin), which are implicated in various biological processes [6]. Recent data suggest a role of dysferlin in the muscle fiber repair process [7][8][9], myoblast differentiation [10], T-tubulogenesis [11], monocyte phagocytosis [12] and muscle regeneration [13]. Dysferlin is predominantly expressed in skeletal and heart muscle, where it localizes to the plasma membrane of muscle fibers [14,15].…”