Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle

Abstract

Aging of skeletal muscle is often accompanied by muscle atrophy and it appears that apoptosis plays an important role in this process. The detailed mechanism(s) is not completely understood, however. In this study, we examined expression of the apoptosis regulatory proteins as well as the heat shock proteins, which have been shown to modulate the apoptotic process in certain cell types, in order to more completely elucidate apoptotic signaling in aged skeletal muscle. To more specifically identify alterations that are likely to be the result of aging, we compared 16-month-old middle-aged (MD) and 29-month-old senescent (SE) male Fischer 344 x Brown Norway rats in our study. Our results show that the degree of DNA laddering was higher in SE compared to MD rats. Using total tissue homogenates we examined the level of expression of several apoptosis-related proteins in two categories: mitochondria-associated proteins and caspases. Of the mitochondria-associated proteins, the levels of p53 showed a significant increase in SE compared to MD rats. There was also a significant increase in the expression of Bax, Bcl-2 and Apaf-1 in SE rats over that of MD rats; cytochrome c and AIF levels remained unchanged, however. Regarding the caspases, there were increases in the levels of pro-caspases-12 and -7 and cleaved caspase-9, although the levels of pro- and cleaved caspase-3 as well as cleaved caspase-12 remained unchanged. Furthermore, our results showed significant increases in HSP27, HSP60, and the inducible HSP70. These data show that in rat skeletal muscle increased apoptosis occurs between middle-age and senescence, indicating an aging-related increase in apoptosis in skeletal muscle. The involvement of different apoptotic pathways in the aging process is suggested by the selective alterations in the apoptosis regulatory proteins. The increased expression of the HSPs suggests a relationship between HSPs and the aging-related apoptotic process.

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

“…Previous studies have demonstrated p53 overexpression in PD brain (De La Monte et al, 1998;Mogi et al, 2007;Da Costa et al, 2009). Additionally, elevated levels of p53 have been shown in aging skeletal muscle leading to muscle atrophy and sarcopenia (Chung and Ng, 2006). These previous reports are consistent with our results that reveal p53 upregulation in the gastrocnemius muscle subsequent to PD induction (De La Monte et al, 1998;Chung and Ng, 2006;Mogi et al, 2007;Da Costa et al, 2009).…”

“…Elevated levels of p53 and active caspase-3 have been reported in many muscular diseases, such as aging skeletal muscle and sarcopenia (Chung and Ng, 2006;Marzetti and Leeuwenburgh, 2006). Moreover, apoptosis has been reported to contribute to the muscle atrophy and loss in muscular diseases (Sandri et al, 1998;Libera et al, 1999;Vescovo et al, 2000;Sandri et al, 2001;Pollack et al, 2002;Dirks and Leeuwenburgh, 2002;Siu and Alway, 2005;Machida and Booth, 2005;Jejurikar et al, 2006;Chung and Ng, 2006;Siu and Alway, 2009;Wohlgemuth et al, 2010;Narasimhan et al, 2014).…”

Multiple Pathways to the Same End: Mechanisms of Myonuclear Apoptosis in Sarcopenia of Aging

“…Elevated cytosolic levels of cytochrome c have been detected in the skeletal muscle of old rats [46]. Accordingly, levels of Apaf-1 [13,46,60], active caspase-9 content [52,54,60], and caspase-9 proteolytic activity [46] were also found to be higher in aged muscles compared to young controls. However, other studies did not observe increases in cytosolic cytochrome c and/or caspase-9 expression in skeletal muscles of old rats [12,13,18,49].…”

“…In fact, increased caspase-12 expression was detected in the skeletal muscle of old rats [13,60,82], suggesting a role for the ER stress response in sarcopenia.…”

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

“…For instance, in the cerebral cortex of Wistar rats, caspase-3 (CASP3) protein expression decreases with aging whereas caspase-8 (CASP8) increases from 12 months of age onwards (Shimohama, Tanino, and Fujimoto 2001). In contrast to the cortex, CASP3 expression levels do not change in the skeletal muscle of aged Fischer 344/Brown Norway rats compared to their younger counterparts (Chung and Ng 2006).…”