Abstract
Myostatin, a member of the transforming growth factor-β superfamily, regulates the glucose metabolism of muscle cells, while dysregulated myostatin activity is associated with a number of metabolic disorders, including muscle cachexia, obesity and type II diabetes. We observed that myostatin induced significant mitochondrial metabolic alterations and prolonged exposure of myostatin induced mitochondria-dependent apoptosis in cancer cells addicted to glycolysis. To address the underlying mechanism, we found that the protein levels of Hexokinase II (HKII) and voltage-dependent anion channel 1 (VDAC1), two key regulators of glucose metabolisms as well as metabolic stress-induced apoptosis, were negatively correlated. In particular, VDAC1 was dramatically upregulated in cells that are sensitive to myostatin treatment whereas HKII was downregulated and dissociated from mitochondria. Myostatin promoted the translocation of Bax from cytosol to mitochondria, and knockdown of VDAC1 inhibited myostatin-induced Bax translocation and apoptosis. These apoptotic changes can be partially rescued by repletion of ATP, or by ectopic expression of HKII, suggesting that perturbation of mitochondrial metabolism is causally linked with subsequent apoptosis. Our findings reveal novel function of myostatin in regulating mitochondrial metabolism and apoptosis in cancer cells.
Highlights
transforming growth factor-b (TGF-b) family members, myostatin binds to the cell surface activin receptor II or IIB (ACTRII, ACTRIIB), which recruits type I receptor ALK 4/5 (Activin receptor-like kinase 4 or 5) to form a complex.[5,6] ALK5, which is involved in the TGF-b signaling pathway, could phosphorylate and activate Smad2/
Received 10.7.12; revised 04.12.12; accepted 16.1.13; Edited by C Munoz-Pinedo cells typically display altered aerobic glycolysis (Warburg effect)[18] and metabolic dysregulation is related to tumor growth and cell death.[19]. We tested this hypothesis and our results demonstrated that myostatin induces metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis in cancer cells and interestingly the chronic exposure of myostatin results in the activation of mitochondria-dependent apoptosis
In an effort to understand the underlying mechanism, we showed that upregulation of VDAC1 and Bax translocation to the mitochondria played critical role in myostatin-induced apoptosis in cancer cells
Summary
TGF-b family members, myostatin binds to the cell surface activin receptor II or IIB (ACTRII, ACTRIIB), which recruits type I receptor ALK 4/5 (Activin receptor-like kinase 4 or 5) to form a complex.[5,6] ALK5, which is involved in the TGF-b signaling pathway, could phosphorylate and activate Smad2/. Emerging evidence has suggested its function in regulating energy metabolism in both muscle and non-muscle cells. Accumulating evidence has demonstrated that dysregulated myostatin is associated with metabolic disorders such as cachexia induced by tumors.[15,16] As most cancer cells express myostatin receptors and several members of Activin/. TGF-b family play very important roles in regulating cell growth, metabolism and apoptosis,[17] it is conceivable to hypothesize that myostatin exerts functional roles in regulating cancer cell growth or death by regulating energy metabolism. This is important since rapidly growing tumor
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