Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.

Aging is associated with the steady decline of several cellular processes. The loss of skeletal muscle mass, termed sarcopenia, is one of the major hallmarks of aging. Aged skeletal muscle exhibits a robust reduction in its regenerative capacity due to dysfunction (i.e., senescence, lack of self-renewal, and impaired differentiation) of resident muscle stem cells, called satellite cells. To replicate aging in vitro, immortalized skeletal muscle cells (myoblasts) can be treated with various agents to mimic age-related dysfunction; however, these come with their own set of limitations. In the present study, we used sequential passaging of mouse myoblasts to mimic impaired differentiation that is observed in aged skeletal muscle. Further, we investigated mitochondrial apoptotic mechanisms to better understand the impaired differentiation in these "aged" cells. Our data shows that sequential passaging (>20 passages) of myoblasts is accompanied with significant reductions in differentiation and elevated cell death. Furthermore, high-passage (HP) myoblasts exhibit greater mitochondrial-mediated apoptotic signaling through mitochondrial BAX translocation, CYCS and AIFM1 release, and caspase-9 activation. Finally, we show that inhibition of mitochondrial outer membrane permeability partly recovered differentiation in HP myoblasts. Together, our findings suggests that mitochondrial apoptotic signaling is a contributing factor to the diminished differentiation that is observed in aged myoblasts.

The Role of Endoscopy for Primary and Secondary Prophylaxis of Variceal Bleeding.

Cirrhosis is associated with a high morbidity and mortality. One of the most serious and unpredictable complication of cirrhosis, with a high mortality rate, is bleeding from esophagogastric varices. Endoscopic screening of varices followed by primary prophylactic treatment with beta blockers or band ligation in the presence of large esophageal varices will reduce the variceal bleeding rates and thereby reduce mortality risks in those with advanced cirrhosis. There is a paucity of data on primary prophylaxis of gastric varices but secondary prophylaxis includes glue injection, balloon-occluded retrograde transvenous obliteration, or transjugular intrahepatic portosystemic shunting with coil embolization.