Suppression of GSK-3β activation by M-cadherin protects myoblasts against mitochondria-associated apoptosis during myogenic differentiation

Abstract

Apoptosis occurs concurrently with differentiation of muscle progenitor cells (MPCs) before they fuse to form myotubes. Dysregulated apoptosis in MPCs contributes to the low regeneration capability in aged muscle and decreases the survival rate of donor cells in stem cell-based therapies for muscular dystrophies. This study investigated the role of the M-cadherin/PI3K/Akt/GSK-3β signaling pathway in regulating apoptosis during differentiation of MPCs. Disruption of M-cadherin-dependent cell-cell adhesion by M-cadherin RNA interference in confluent C2C12 myoblasts sensitized the cells to mitochondria-associated intrinsic apoptosis induced by cell confluence or serum starvation. Further investigation of this pathway revealed that M-cadherin-mediated signaling suppressed GSK-3β activation by enhancing the PI3K/AKT-dependent inhibitory phosphorylation of Ser9 in GSK-3β. Overexpression of wild-type GSK-3β in confluent C2C12 myoblasts exacerbated the apoptosis, whereas chemical inhibition of GSK-3β using TDZD-8, or forced expression of constitutively active Akt (myrAkt), or a kinase-deficient GSK-3β mutant [GSK-3β(K85R)], attenuated apoptosis and rescued the impaired myogenic differentiation that is caused by M-cadherin RNA interference. These data suggest that M-cadherin-mediated signaling prevents acceleration of mitochondria-associated intrinsic apoptosis in MPCs by suppressing GSK-3β activation during myogenic differentiation.

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…In contrast, a study designed to investigate the mitochondrial dysfunction during fasting concluded it was a consequence rather than a cause of insulin resistance (Hoeks et al, 2010). Indeed, when associated with cell death or apoptosis, mitochondrial dysfunction is reported to occur after GSK-3␤ activation (Petit-Paitel et al, 2009;Wang et al, 2011), placing it after insulin resistance (Fig. 1).…”

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

“…However, there is evidence that apoptotic signaling in myonuclei and satellite cells may have a role in regulating muscle loss in response to forced disuse (Alway et al, 2014a; Alway et al, 2015; Alway et al, 2011; Alway et al, 2014b; Hao et al, 2011; Marzetti et al, 2013a; Marzetti et al, 2012; Wang et al, 2011). Loss of autophagy signaling in satellite cells/muscle stem cells in aging muscle (Garcia-Prat et al, 2016; Sousa-Victor et al, 2014) might increase the susceptibility of satellite cells for apoptosis and reduce the regenerative capacity of muscle.…”

“…Mitophagy is the selective removal of dysfunctional mitochondria by autophagic processes (Pryde et al 2016; Wang et al 2011) that requires tagging of dysfunctional mitochondria so that they can be recognized for disassembly. The selectivity of mitophagy is controlled by the loss of the mitochondrial membrane potential (Δψm) and by several important proteins such as BCL2 interaction myosin/moesin like coiled-coil protein 1 (Beclin1), in conjugation with autophagy-related gene (ATG) family members which support lipidation of microtubule associated protein light chain 3 (LC3)-I to LC3-II.…”

“…Dysfunctional mitochondria are engulfed in the double membrane autophagosome (Amaya et al, 2015; Levine et al, 2015). The autophagosome fuses with a lysosome, and the proteolytic contents of the lysosome are emptied into the autophagosome, which then digests the dysfunctional mitochondria (Pryde et al 2016; Wang et al 2011). …”

Cardiac and mitochondrial dysfunction following acute pulmonary exposure to mountaintop removal mining particulate matter

“…Terminal dUTP nick-end labeling (TUNEL) was performed to detect apoptotic nuclei in tissue cross sections, as previously described (32, 74). Briefly, frozen tissue (10 μm thick) cross sections of left ventricle were mounted on charged microscope slides (Fisher Scientific, Pittsburgh, PA), air dried, and incubated overnight at 4°C with mouse anti-heavy chain cardiac myosin antibody (no.…”