Myostatin induces mitochondrial metabolic alteration and typical apoptosis in cancer cells

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.

Myostatin regulates miR-431 expression via the Ras-Mek-Erk signaling pathway

“…A functional role for MSTN in regulating myogenic development was further supported by the phenotypes associated with naturally occurring mutations of the MSTN gene in cattle and humans [2,3]. Recent studies have demonstrated non-muscle functions of MSTN in the regulation of adipogenesis [4,5], cardiac myocyte hypertrophy [6] and glucose metabolism [7], and cancer cell apoptosis [8]. Given the profound biological significance of MSTN, there is considerable interest in identifying the molecular mechanisms underlying MSTN-regulated cellular responses.…”

Mild mitochondrial metabolic deficits by α-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease

“…Release of cytochrome c can induce non-specific autophagy within the cell. Several different mechanisms can trigger the release of cytochrome c: CL peroxidation, leakage through the mitochondrial permeability transition (MPT) pore complex, Bax and Bak interactions with voltage-dependent anion channel (VDAC), and high K + level in extra-mitochondrial matrix (Gogvadze et al, 2006; Liu et al, 2013; Tan et al, 2005). …”

ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

“…Western blotting was performed accordingly to the methods described previously [21]. Cells or nuclear fractions were lysed in lysis buffer (10 mM HEPES, pH 7.4, 2 mM EGTA, 0.5% NP-40, protease inhibitors).…”