Muscle fiber‐specific apoptosis and TNF‐α signaling in sarcopenia are attenuated by life‐long calorie restriction

Abstract

Increased tumor necrosis factor-alpha (TNF-alpha) levels have been found with age and are connected to muscle atrophy and cell loss, yet the signaling events that occur in vivo are unknown. Calorie restriction (CR), a robust intervention shown to repeatedly evade the physiological declines associated with aging, has been reported to reduce TNF-alpha and may assist in understanding the mechanisms of muscle sarcopenia. The effects of age and CR on muscle mass, myocyte area, fiber number, myocyte TNF-alpha expression, plasma TNF-alpha levels, and specific elements linked with the TNF-alpha signaling cascade (TNF-R1, IKKgamma, IkappaBalpha, p65, NF-kappaB binding activity, FADD, caspase-8, and DNA fragmentation) were investigated in soleus (predominately Type I fiber), and superficial vastus lateralis (SVL, predominately Type II fiber), of 6-month-old ad libitum fed (6AL), 26-month-old ad libitum fed (26AL), and 26-month-old calorie-restricted (26CR) male Fischer 344 rats (CR = 40% restriction compared with ad libitum). Plasma TNF-alpha was increased with age, and the age-associated rise was attenuated with life-long CR. In soleus muscle, we reported a greater capacity to cultivate inflammatory signaling through the transcription factor NF-kappaB compared with that detected in SVL with age. In contrast, in the SVL TNF-alpha stimulated apoptotic signaling with age to a much higher extent than was observed in the soleus. Moreover, a reduction in muscle mass, cross-sectional area, and fiber number in the SVL coincided with this age-linked elevation in apoptosis. In agreement with CR's ability, TNF-alpha stimulation of both inflammatory and apoptotic pathways were abrogated. Our results suggest that TNF-alpha signals transmitted to specific fiber types determine the decision of selecting life or death signaling pathways and are linked to the extent of fiber loss experienced in the aging muscle. Such a specific potential may constitute a major proponent in the pathogenesis of sarcopenia.

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

“…Our observations of potential muscle and/or fiber type specific differences in TNF-α associated apoptotic signaling differs from data reported by Phillips and Leeuwenburgh [25], who did not find differences in the expression of apoptotic markers between the soleus (primarily a type I fibered muscle) and the superficial vastus lateralis muscles (primarily a type II fibered muscle) of aged rats. These disparate findings may be due to the different strains and ages of rodents utilized in our study and the previous study [25].…”

“…These disparate findings may be due to the different strains and ages of rodents utilized in our study and the previous study [25]. Despite these differences, the data from our study and that of Phillips and Leeuwenburgh [25] suggest that the extrinsic apoptotic pathway is active in skeletal muscle of aged rodents and this may contribute to age-associated muscle loss via increases in apoptotic signaling.…”

“…The contribution of the extrinsic apoptotic pathway to skeletal muscle mass losses, especially during aging, has been less studied [25]. The increase in circulating concentrations of the cytokine, tumor necrosis factor-alpha (TNF-α), may initiate proapoptotic signaling upon binding to the type I TNF receptor (TNFR).…”

Genes regulated by caloric restriction have unique roles within transcriptional networks

“…An alternative possibility is that CR activates Sirt1, which then deacetylases components of the NF-κB complex (Yeung et al, 2004b;Ghosh et al, 2007;Salminen et al, 2008; but see Barger et al, 2008). Previous studies have indeed found that NF-κB signaling is inhibited by caloric restriction in both rodents and humans (Phillips and Leeuwenburgh, 2005;Dirks and Leeuwenburgh, 2006;Weiss et al, 2006;Ugochukwu and Figgers, 2007), and that inhibition of NF-κB blocks the accumulation of beta-amyloid plaques in Alzheimer's mice (Paris et al, 2007), as well as neoplastic transformation of cells during the initial stages of cancer (Karin, 2006). Such effects result from blocking NF-κB activation, which is a characteristic feature of normal aging, as demonstrated by a recent genomic study (Adler et al, 2007).…”

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

“…In particular, the death receptor-mediated pathway, triggered by TNF-α, is thought to play a significant role in age-related muscle loss [14,17,19,20], owing to its ability to promote muscle protein wasting [63,64] and myonuclear apoptosis [14,17,19,20,65]. Interestingly, the transduction of TNF- α signaling during aging may be fiber-type specific[14]. In fact, TNF- α-mediated apoptosis was enhanced at old age in the rat superficial vastus lateralis muscle (predominantly comprised of type II fibers), whereas increased signaling through the NF-κB pathway was observed in the soleus muscle, characterized by type I fiber dominance.…”