Myoferlin regulation by NFAT in muscle injury, regeneration and repair

Abstract

Ferlin proteins mediate membrane-fusion events in response to Ca(2+). Myoferlin, a member of the ferlin family, is required for normal muscle development, during which it mediates myoblast fusion. We isolated both damaged and intact myofibers from a mouse model of muscular dystrophy using laser-capture microdissection and found that the levels of myoferlin mRNA and protein were increased in damaged myofibers. To better define the components of the muscle-injury response, we identified a discreet 1543-bp fragment of the myoferlin promoter, containing multiple NFAT-binding sites, and found that this was sufficient to drive high-level myoferlin expression in cells and in vivo. This promoter recapitulated normal myoferlin expression in that it was downregulated in healthy myofibers and was upregulated in response to myofiber damage. Transgenic mice expressing GFP under the control of the myoferlin promoter were generated and GFP expression in this model was used to track muscle damage in vivo after muscle injury and in muscle disease. Myoferlin modulates the response to muscle injury through its activity in both myoblasts and mature myofibers.

NRIP is a novel Z-disc protein to activate calmodulin signaling for skeletal muscle contraction and regeneration

“…NRIP can stimulate CaN-NFAT and CaMKII, which are involved in muscle regeneration after muscle injury or degeneration (Abraham and Shaw, 2006;Michel et al, 2004). For example, CaN and/or NFAT functions are blocked by a negative regulator (myospryn) or immunosuppressive drugs (cyclosporine A), leading to the impairment of muscle regeneration (Demonbreun et al, 2010;Kielbasa et al, 2011). Moreover, CaN transgenic mice display strong regeneration of skeletal muscle fibers after injury (Demonbreun et al, 2010;Stupka et al, 2006).…”

“…For example, CaN and/or NFAT functions are blocked by a negative regulator (myospryn) or immunosuppressive drugs (cyclosporine A), leading to the impairment of muscle regeneration (Demonbreun et al, 2010;Kielbasa et al, 2011). Moreover, CaN transgenic mice display strong regeneration of skeletal muscle fibers after injury (Demonbreun et al, 2010;Stupka et al, 2006). In addition, the CaMK pathway can be activated by treatment with insulin-like growth factor 1 (IGF1), which has been well documented to activate satellite cells and to induce terminal myogenic differentiation (Lu et al, 2000;Song et al, 2013).…”

“…Compelling evidence shows that the CaN and CaMKII signaling pathways are involved in muscle repair and muscle regeneration (Demonbreun et al, 2010;McKinsey et al, 2000). Muscle degeneration and regeneration are tightly regulated in response to muscle injury.…”

“…Then, satellite cells are activated and proliferate, and then transform into myoblasts. Sequentially, these myoblasts move to the site of the lesion to fuse with pre-existing myofibers or to form new myotubes for muscle regeneration (Borselli et al, 2010;Demonbreun et al, 2010;Mokalled et al, 2012;Shi and Garry, 2006).…”

“…Both CaN and CaMKII have been reported to be involved in muscle regeneration after muscle injury (Abraham and Shaw, 2006;Demonbreun et al, 2010). To investigate extensively the potential role of NRIP in muscle regeneration, wild-type and NRIP-knockout mice were injected with cardiotoxin (CTX) unilaterally into the tibialis anterior muscle, the contralateral muscle was injected with PBS as a control (Frey et al, 2008).…”