| Skeletal muscle atrophy is the loss of muscle mass and strength,and associated with the increase of incidence rate of chronic diseases and all-cause mortality,which is mainly caused by nerve injury,aging,cachexia and the disuse.When muscle atrophy occurs,inflammation,fibrosis,cell apoptosis and abnormal autophagy occur,with insufficient proliferation and differentiation ability of muscle stem cells,leading to difficulty in restoring muscle function.Currently,the therapy of muscle atrophy is limited.It is urgent to investigate novel molecules to attenuate muscle atrophy.AGGF1 is an angiogenic factor found in patients with KTS syndrome.It regulates the differentiation,proliferation,migration,endoplasmic reticulum stress and other functions in endothelial and smooth muscle cells,promotes angiogenesis and treats cardiovascular diseases,but its role in skeletal muscle is still unknown.This study used molecular,cellular experiments,and animal models.The main results are as follows:we identified AGGF1 is an important protective factor against muscle atrophy.Firstly,the expression of AGGF1 was significantly increased in the muscle of patients with lumbar disc herniation,but it is insufficient to inhibit muscle atrophy.Extra AGGF1 protein treatment inhibited muscle atrophy,with decreased the ubiquitin ligase Mu RF1 expression,but not the other ubiquitin ligase MAFbx.However,AGGF1 did not promote muscle cell proliferation.Secondly,the expression of AGGF1 in muscle atrophy was significantly increased in denervation and cancer cachexia mouse models.Thirdly,in order to confirm the role of AGGF1 in muscle atrophy,this study found that Aggf1+/-mice in 7 days denervation and cancer cachexia models showed more severe muscle inflammation,fibrosis and atrophy,with accelerated degradation of My HC andα-actin via activation of NF-κB and Mu RF1,as well as inhibited autophagy-related protein LC-3B.Although Aggf1+/-mice did not show muscle atrophy after 2 days denervation,muscle inflammation and fibrosis were more severe,with elevated expression of NF-κB and Mu RF1,as well as inhibited autophagy.Lastly,AGGF1 protein plays a protective role in denervation and cachexia mouse models.AGGF1 inhibited muscle inflammation,fibrosis,and atrophy in 7 days denervation and cancer cachexia models,with increased expression of My HC andα-actin via reduction of NF-κB and Mu RF1,as well as activated autophagy.AGGF1 also inhibited muscle inflammation and fibrosis in 2 days denervation model,with decreased expression of NF-κB and Mu RF1,as well as activated autophagy.Further research was conducted on the molecular mechanism by which AGGF1 inhibits muscle atrophy.TWEAK is a weak apoptosis inducing factor in the TNF family,and its overexpression exacerbates denervated muscle atrophy.This study found that AGGF1interacted with TWEAK in both mouse atrophy muscle and C2C12 cells,and inhibited NF-κB activation via reducing the binding of TWEAK and Fn14.The interaction between TWEAK and Fn14 enhanced in atrophy muscle in Aggf1+/-mice.AGGF1 protein reduced the interaction between TWEAK and Fn14 in atrophy muscle.Secondly,AGGF1 inhibited Caspase-3 and PARP1 activation,collagen I and collagen III accumulation resulting in reduction of muscle inflammation and fibrosis.Besides,AGGF1 promotes autophagy by upregulating LC-3B via JNK phosphorylation.In conclusion,this study found that AGGF1 is a key regulatory factor in inhibiting muscle atrophy and demonstrated its molecular mechanism.AGGF1 injection is a potential method for treating muscle atrophy. |
