Abstract
In the context of normal cell turnover, apoptosis is a natural phenomenon involved in making essential life and death decisions. Apoptotic pathways balance signals which promote cell death (pro-apoptotic pathways) or counteract these signals (anti-apoptotic pathways). We proposed that changes in anti-apoptotic proteins would occur during mammalian hibernation to aid cell preservation during prolonged torpor under cellular conditions that are highly injurious to most mammals (e.g. low body temperatures, ischemia). Immunoblotting was used to analyze the expression of proteins associated with pro-survival in six tissues of thirteen-lined ground squirrels, Ictidomys tridecemlineatus. The brain showed a concerted response to torpor with significant increases in the levels of all anti-apoptotic targets analyzed (Bcl-2, Bcl-xL, BI-1, Mcl-1, cIAP1/2, xIAP) as well as enhanced phosphorylation of Bcl-2 at S70 and T56. Heart responded similarly with most anti-apoptotic proteins elevated significantly during torpor except for Bcl-xL and xIAP that decreased and Mcl-1 that was unaltered. In liver, BI-1 increased whereas cIAP1/2 decreased. In kidney, there was an increase in BI-1, cIAP and xIAP but decreases in Bcl-xL and p-Bcl-2(T56) content. In brown adipose tissue, protein levels of BI-1, cIAP1/2, and xIAP decreased significantly during torpor (compared with euthermia) whereas Bcl-2, Bcl-xL, Mcl-1 were unaltered; however, Bcl-2 showed enhanced phosphorylation at Thr56 but not at Ser70. In skeletal muscle, only xIAP levels changed significantly during torpor (an increase). The data show that anti-apoptotic pathways have organ-specific responses in hibernators with a prominent potential role in heart and brain where coordinated enhancement of anti-apoptotic proteins occurred in response to torpor.
Highlights
The cellular pathways which regulate programmed cell death have long been recognized as important biological processes
Cellular mechanisms employed by squirrels that counter, for example, the damaging effects of low body temperatures, ischemia/reperfusion, or muscle disuse could help biomedical researchers to design new preservation techniques to use in tissue/organ storage and transplantation or identify new therapeutic targets for counteracting effects of hypothermia, reperfusion injury, metabolic diseases, atrophy, etc
Heart must continue to pump throughout, adjusting to both low body temperature and the increase in force of contraction needed at low heart rates and high blood viscosities during torpor (Dawe & Morrison, 1955; Fahlman, Storey & Storey, 2000; Brauch et al, 2005)
Summary
The cellular pathways which regulate programmed cell death have long been recognized as important biological processes. Dysregulation of the molecular signals responsible for promoting versus inhibiting apoptosis has been linked to various disease or degenerative states including atrophy and cancer (Siu, 2009; Strasser, Cory & Adams, 2011). The mitochondria lie upstream of irreversible cellular damage and local proteins play roles in either the inhibition or promotion of MOMP (Fig. 1) (Estaquier et al, 2012). Other local proteins, including BI-1 (Bax inhibitor-1), regulate cell death via inhibition of pro-apoptotic Bcl-2 members, but are linked with endoplasmic reticulum (ER) stress (Ishikawa et al, 2011). Additional pro-survival members such as the inhibitor of apoptosis protein (IAP) family, including cIAP1/2 and xIAP, function by interfering with caspase activation as well as by playing a role in NFκB signal transduction (Gyrd-Hansen & Meier, 2010)
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