Coupling Endoplasmic Reticulum Stress to the Cell Death Program MECHANISM OF CASPASE ACTIVATION

Sarcopenia may be partly due to a loss in total fiber number by apoptosis We have investigated age-related alterations in the mitochondria-mediated pathway leading to apoptosis in the gastrocnemius muscle from 6-mo-old and 24-mo-old male Fisher 344 rats Apoptosis (mono- and oligonucleosome fragmentation) in the gastrocnemius muscle was increased by 50% in the old rats compared with the adult animals Furthermore, there was a significant correlation between cytosolic cytochrome c and caspase-3 activity, although neither cytochrome c nor caspase-3 activity increased significantly with age Furthermore, there was a significant correlation between caspase-3 activity and mono- and oligonucleosome fragmentation in the old rats only Mitochondrial Bcl-2 and Bax were not altered with age In vitro experiments demonstrated that activation of the caspase cascade in skeletal muscle might be limited by procaspase-9 activation This is the first study to explore the role of apoptosis in sarcopenia and suggests that subtle changes in apoptosis are involved

/pdf/apoptosis-in-skeletal-muscle-with-aging-2nxxxj948s.pdf

Apoptosis in skeletal muscle with aging

Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been a major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivors, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular late-onset cardiomyopathy. Although intensive investigations on DOX-induced cardiotoxicity have continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports the notion that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and that other types of cell death, such as autophagy and senescence/aging, may participate in this process. This review focuses on the current understanding of the molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. The different sensitivities to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed.

/pdf/cardiomyocyte-death-in-doxorubicin-induced-cardiotoxicity-28zx33q0b3.pdf

Cardiomyocyte death in doxorubicin-induced cardiotoxicity

Mitochondria play a critical role in apoptosis induction in response to myriad stimuli. These organelles release proteins into the cytosol which trigger caspase activation or perform other functions relevant to apoptosis, including cytochrome c (cyt-c), caspases, AIF, and SMAC (Diablo). The mechanisms by which these proteins escape from mitochondria remain enigmatic. Moreover, it is unclear whether release of these proteins versus disturbances in core mitochondrial functions represents the cell death commitment mechanism. In this regard, suppression of apoptosis using broad-spectrum caspase inhibitory compounds has been reported in many circumstances to prevent the morphological and biochemical manifestations of apoptosis, and yet not protect cells from death and not preserve clonigenic survival. Thus, while mitochondrial damage can be coupled to caspase activation pathways, cell death commitment often occurs upstream of caspase activation when mitochondria-dependent cell death pathways are invoked. Here, we review evidence implicating dysregulation of cellular pH as a component of the cell death mechanism involving mitochondria. Cell Death and Differentiation (2000) 7, 1155 - 1165

http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-2417.pdf

Mitochondria-dependent apoptosis and cellular pH regulation.

Apoptosis in Human Disease: A New Skin for the Old Ceremony?

Apoptotic regulatory mechanisms in skeletal muscle have not been revealed. This is despite indications that remnant apoptotic events are detected following exercise, muscle injury and the progression of dystrophinopathies. The recent elicitation of a cytochrome c-mediated induction of caspases has led to speculation regarding a cytochrome c mechanism in muscle. We demonstrate that cytosols from skeletal muscle biopsies from healthy human volunteers lack the ability to activate type-II caspases by a cytochrome c-mediated pathway despite the confirmed presence of both procaspase-3 and -9. This was not due to the presence of an endogenous inhibitor, as the muscle cytosols enhanced caspase activity when added to a control cytosol, subsequently activated by cytochrome c and dATP. In addition, we demonstrate that muscle cytosols lack the apoptosis protease activator protein-1 (APAF-1), both at the protein and mRNA levels. These data indicate that human skeletal muscle cells will be refractory to mitochondrial-mediated events leading to apoptosis and thus can escape a major pro-apoptotic regulatory mechanism. This may reflect an evolutionary adaptation of cell survival in the presence of the profusion of mitochondria required for energy generation in motility.

/pdf/human-skeletal-muscle-cytosols-are-refractory-to-cytochrome-42rz3vhyuy.pdf

Human skeletal muscle cytosols are refractory to cytochrome c-dependent activation of type-II caspases and lack APAF-1.

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Human skeletal muscle cytosols are refractory to cytochrome c-dependent activation of type-II caspases and lack APAF-1.