Short-term caloric restriction, resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber-type specific manner in aged animals

Abstract

Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR + RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 × Brown Norway rats. CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR + RSV) paradigms showed a protective effect in the soleus and plantaris muscle (P < 0.05). Sirt1 protein content was increased by 2.6-fold (P < 0.05) in WG but not RG muscle with RSV treatment, while CR or CR + RSV had no effect. PGC-1α levels were higher (2-fold) in the WG from CR-treated animals (P < 0.05) when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment. Levels of the anti-apoptotic protein Bcl-2 were significantly higher (1.6-fold) in the WG muscle of RSV and CR + RSV groups compared to AL (P < 0.05) but tended to occur coincident with elevations in the pro-apoptotic protein Bax so that the apoptotic susceptibility as indicated by the Bax to Bcl-2 ratio was unchanged. There were no alterations in DNA fragmentation with any treatment in muscle from older animals. Additionally, mitochondrial respiration measured in permeabilized muscle fibers was unchanged in any treatment group and this paralleled the lack of change in cytochrome c oxidase (COX) activity. These data suggest that short-term moderate CR, RSV, or CR + RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study.

Nutritional supplementations and administration considerations for sarcopenia in older adults

“…In fact 10-month resveratrol supplementation of middle-aged mice was effective in preserving the fast-twitch muscle fiber function and age related oxidative stress, however it could not prevent muscle mass loss in these animals [107]. Although the result of this study in regard to the effect of resveratrol on muscle mass was in agreement with Joseph et al [101], different fiber types were responsive to the beneficial effects of resveratrol supplementation in these studies. Therefore, it is not clear whether the effect of resveratrol is fiber-specific and if so, which fiber types are more responsive to this treatment.…”

“…Supplementing old (27 month-old) male rats with 50 mg/kg/day resveratrol for 6 weeks enhanced sirtuin 1 (SIRT1), a histone residue deacetylase which is supposed to be associated with increased longevity and aging suppression [102], in slow-twitch gastrocnemius muscle fibers. However, the resveratrol supplementation regimen did not have any impact on oxidative stress markers and muscle mass [101]. Nonetheless, the increase in SIRT1 activity was also shown in a study conducted by Zheng et al [98] that has been discussed earlier in this section.…”

“…Ingestion of higher doses, 12.5 mg/kg/day, of resveratrol for 21 days in older rats (34 month-old), who received hind limb suspension for 14 days during the course of the study, was shown to affect oxidative stress markers by increasing catalase and manganese SOD (MnSOD) activities and decreasing lipid peroxidation and hydrogen peroxide contents in gastrocnemius muscle [100]. Although Jackson et al [100] examined the gastrocnemius muscle as a whole, without having concern about different fiber types, a later study by the same research group [101] demonstrated that slow-twitch, gycolytic gastrocnemius muscle fibers are more responsive to resveratrol than fast-twitch, oxidative fibers in gastrocnemius muscle. Supplementing old (27 month-old) male rats with 50 mg/kg/day resveratrol for 6 weeks enhanced sirtuin 1 (SIRT1), a histone residue deacetylase which is supposed to be associated with increased longevity and aging suppression [102], in slow-twitch gastrocnemius muscle fibers.…”

Exogenous nicotinamide supplementation and moderate physical exercise can attenuate the aging process in skeletal muscle of rats

“…It is made from L-tryptophan through kynurenine. Besides being important to NAD synthesis, NAM can inhibit the activity of SIRT1, the enzyme which appears to be important in a wide range of physiological processes including mitochondrial biogenesis (Koltai et al 2012), DNA repair (Sarga et al 2013), metabolism (MoralesAlamo and Calbet 2016) and apoptosis (Joseph et al 2013;Radak et al 2013), among others.…”

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

“…In rats, resveratrol supplementation prevented age-induced muscle loss (Jang et al 2012;Joseph et al 2013), suppressed pro-apoptotic signaling in senescent heart and prevented age-related heart dysfunction (Sin et al 2014). Moreover, supplementation with polyphenol-rich blueberries increased IGF-1 expression in hippocampus of aged rats, improving hippocampal plasticity and memory performances (Casadesus et al 2004).…”