p38 MAPK Participates in Muscle-Specific RING Finger 1-Mediated Atrophy in Cast-Immobilized Rat Gastrocnemius Muscle

Abstract

Skeletal muscle atrophy is a common phenomenon during the prolonged muscle disuse caused by cast immobilization, extended aging states, bed rest, space flight, or other factors. However, the cellular mechanisms of the atrophic process are poorly understood. In this study, we investigated the involvement of mitogen-activated protein kinase (MAPK) in the expression of muscle-specific RING finger 1 (MuRF1) during atrophy of the rat gastrocnemius muscle. Histological analysis revealed that cast immobilization induced the atrophy of the gastrocnemius muscle, with diminution of muscle weight and cross-sectional area after 14 days. Cast immobilization significantly elevated the expression of MuRF1 and the phosphorylation of p38 MAPK. The starvation of L6 rat skeletal myoblasts under serum-free conditions induced the phosphorylation of p38 MAPK and the characteristics typical of cast-immobilized gastrocnemius muscle. The expression of MuRF1 was also elevated in serum-starved L6 myoblasts, but was significantly attenuated by SB203580, an inhibitor of p38 MAPK. Changes in the sizes of L6 myoblasts in response to starvation were also reversed by their transfection with MuRF1 small interfering RNA or treatment with SB203580. From these results, we suggest that the expression of MuRF1 in cast-immobilized atrophy is regulated by p38 MAPK in rat gastrocnemius muscles.

Differential Regulation of MAPK Isoforms during Cast-Immobilization -Induced Atrophy in Rat Gastrocnemius Muscle

“…Some investigators have shown that muscle atrophy is mediated by both the PKB/Akt and SAPK/JNK pathways and that the atrophy-associated induction of atrogin-1 is regulated by the inhibition of PKB/ Akt activation 3,22,24) . Furthermore, it has been reported that upregulation of atrogin-1 and MuRF-1 in atrophied muscles are mediated by p38 MAPK and NF-κb, respectively 16,25,26) . However, the relationship between muscle atrophy and the phosphorylation of ERK1/2, p38 MAPK, SAPK/ JNK, and PKB/Akt has not been clearly determined.…”

“…These results are consistent with the atrophy characteristics presented in previous reports on rat skeletal muscles [20][21][22] . Both MuRF-1, which contains a RING-finger domain, and atrogin-1/MAFbx, which contains an F-box domain, are E3 ubiquitin ligases, which are known to initiate ATP-dependent ubiquitinmediated proteolysis and promote skeletal muscle atrophy 16,23,25) . Further, MuRF-1 and atrogin-1/ MAFbx are known to be major factors mediating muscle atrophy in a variety of cells and tissues 22,25) .…”

“…Both MuRF-1, which contains a RING-finger domain, and atrogin-1/MAFbx, which contains an F-box domain, are E3 ubiquitin ligases, which are known to initiate ATP-dependent ubiquitinmediated proteolysis and promote skeletal muscle atrophy 16,23,25) . Further, MuRF-1 and atrogin-1/ MAFbx are known to be major factors mediating muscle atrophy in a variety of cells and tissues 22,25) . Some investigators have shown that muscle atrophy is mediated by both the PKB/Akt and SAPK/JNK pathways and that the atrophy-associated induction of atrogin-1 is regulated by the inhibition of PKB/ Akt activation 3,22,24) .…”

“…SAPK/JNK and p38 MAPK are also activated by exposure to environmental stress or stress signals such as muscle damage, pathologic state, and stretching of skeletal muscle 11) . We previously reported that the starvation-induced e l e v a t i o n o f M u R F -1 ex p r e s si o n i n c a stimmobilized muscle tissues and cells is regulated by p38 MAPK 25) . However, the differential functions of MAPK isoforms in skeletal muscle dysfunction, especially during atrophy, are not fully understood.…”

Chrysanthemum borealeflower floral water inhibits platelet-derived growth factor-stimulated migration and proliferation in vascular smooth muscle cells

“…Mitogen-activated protein kinases (MAPKs) are also signaling molecules important for regulating various cellular processes in cells, including proliferation, differentiation, and migration (Kim et al, 2009;Lee et al, 2008a,b). MAPK activation is induced by diverse stimuli, including growth factors, hormones, and cytokines .…”