Pretreatment with insulin-like growth factor I protects skeletal muscle cells against oxidative damage via PI3K/Akt and ERK1/2 MAPK pathways

Abstract

Oxidative stress has an important role in the pathogenesis of many muscle diseases. The major contributors to oxidative stress in muscle tissue are reactive oxygen species such as oxygen ions, free radicals, and peroxides. Insulin-like growth factor I (IGF-I) has been shown to increase muscle mass and promote muscle cell proliferation, differentiation, and survival. We, therefore, hypothesized that IGF-I might also be cytoprotective for muscle cells during oxidative stress. Exogenous hydrogen peroxide (H 2 O 2 ) was used to induce oxidative stress/damage in two types of skeletal muscle cells. Apoptotic pathways were assessed after the oxidative damage and the effects of IGF-I on oxidative stress in muscle cells were examined. Different IGF-I sub-pathways were analyzed with measurement of the expression of pro-and antiapoptotic proteins. It was found that H 2 O 2 diminishes muscle cell viability and induces a caspase-independent apoptotic cell death. Pretreatment with IGF-I protects muscle cells from H 2 O 2 -induced cell death and enhances muscle cells survival. This effect appears to result from the promotion of the anti-apoptotic protein, Bcl2. Further investigation shows that protection is via an IGF-I sub-pathway: PI3K/Akt and ERK1/2 MAPK pathways. Protecting muscle cells from oxidative damage presents a potential application in the treatment of the muscle wasting, which appears in many muscle pathologies including Duchenne muscle dystrophy and sarcopenia. Many pathological muscle conditions, such as Duchenne muscle dystrophy (DMD) and sarcopenia, have been found to be associated with an increase in oxidative stress. 1 DMD is a severe progressive X-linked muscle disease with the absence of dystrophin, a protein providing structural integrity on the muscle cell membrane. Owing to the fragility of the DMD muscle membrane, normal muscular contraction in DMD destabilizes the myocyte membrane, causing intracellular accumulation of calcium. This stimulates oxidative metabolism, which generates free radicals and triggers the key pathological processes. 2 Sarcopenia is a condition with degenerative loss of skeletal muscle mass and strength associated with ageing. Mitochondrial (Mt) production of reactive oxygen species (ROS) has been shown to increase in skeletal muscle over the course of ageing, 3 which in turn reduces bioenergetic efficiency and leads to muscle fiber atrophy/loss. 4 Although DMD and sarcopenia have different pathological properties, they share a common syndrome, that is, muscle wasting. Abundant evidence implicates oxidative stress as a potential regulator of proteolytic pathways leading to muscle wasting. 5 Oxidative stress results from the activities of the reactive compounds called ROS. ROS are natural by-products in the normal metabolism of oxygen and have important roles in cell signalling. ROS including oxygen ions, free radicals, and peroxides usually have highly reactive properties because of the presence of unpaired valence shell electrons. During physiological homeostasis overall oxidati...

An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms

“…This suggests that the decrease in fatty acid unsaturation and oxidative stress induced by atenolol can also be due to changes in gene expression activated by increases in ERK-dependent signaling. In relation to this, recent studies in skeletal muscle cells show that protection against exogenous hydrogen peroxide by IGF-1 pretreatment is brought about in part by the MAPK/ERK pathway, highlighting the relationship between this signaling pathway and lowering of oxidative stress (Yang et al 2010). …”

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

“…On the other hand, the ability of IGF-1 to prevent and counteract ROS formation and damage has been shown [51,94,[114][115][116][117]190] and is mediated by NF-κB (nuclear factor κB) activation and p53 inhibition, via PI3K [191], mitochondrial stabilization [192], antiapoptosis [187,193] and DNA repair [117] or sirtuin activation [194]. One drug able to elicit these specific IGF-1 properties is metformin [195], which has been shown to improve cardiovascular outcomes in diabetic patients [196].…”

Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

“…This suggested a functional role for Shh in controlling the fate of skeletal muscle cells. Some studies have indicated that the PI3K/AKT pathway regulates cell survival through Bcl2 family proteins [45, 46]. Recently, the protective effect of Shh has been attributed to activation of the PI3K/AKT/Bcl2 pathway [47].…”

“…Therefore, we suggest that Shh prevents apoptosis in skeletal muscle, in part, through the AKT/mTOR/p70S6K pathway. Nevertheless, these results cannot rule out the possibility of crosstalk between Shh and other pathways in regulating skeletal muscle apoptosis for limited information, such as the ERK1/2 MAPK signaling pathway [46]. The underlying mechanism by which Shh modulates apoptosis in skeletal muscle needs to be further studied.…”