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.
It is well established that impairments in mitochondrial function/regulation contribute to tissue decline with aging. Caloric restriction (CR) and resveratrol (RSV) treatment in rodents induces beneficial mitochondrial adaptations in tissues such as heart and skeletal muscle but whether similar benefits occur in fat is unknown. Thus, we investigated whether RSV (50 mg/kg/day; 6 weeks) and/or CR (20% reduced AL; 6 weeks) could alter mitochondrial regulation/biogenesis in aged rodent adipose tissues (visceral; VIS, epididymal; EPI, brown adipose tissue; BAT). Aged F344xBN rats (26 mo) were divided into 4 groups (n=4): ad libitum (AL), CR, RSV, RSV+CR and mitochondrial content (cyto c, COX activity, and COX I) and mitochondrial signaling/regulation (AMPK, PGC‐1α) were assessed. Expectedly, mitochondrial content (cyto c, COX activity) and PGC‐1α were significantly elevated (~2–3‐fold) in the BAT compared to EPI and VIS fat. CR and RSV tended to increase COX activity (~20–50%) in all adipose depots but showed inconsistencies with other mitochondrial content/signaling markers. Interestingly, combined CR and RSV treatment had no effect and/or suppressed COX activity in all adipose tissues. Our data indicates that short‐term CR and RSV treatment when applied independently appears to enhance mitochondrial content in adipose tissue and may contribute to improvements in health associated with these paradigms.
The mitochondrial theory of aging proposes that mitochondrial DNA mutations (mtDNA) accumulate with age and this leads to mitochondrial dysfunction and/or damage that contribute to the aging process. mtDNA mutator mice (referred to as PolG) contain a deficient version of the proofreading mtDNA polymerase gamma and consequently incur high mutation rates to mtDNA that lead to mitochondrial dysfunction. As a result of these spontaneous mutations, PolG mice have an accelerated aging phenotype, allowing their use as a model of aging. The present study investigated the effect of increased mtDNA mutations on regulators of skeletal muscle mitochondrial biogenesis and morphology in young (3–6 mo) and old (8–15 mo) PolG and wild‐type (WT) mice. In old animals, mtDNA content was significantly reduced in the PolG compared to WT. Moreover, there was an age‐dependent decrease in PGC‐1α levels exhibited in both PolG and WT animals. However, young mice with the PolG mutation contained a greater level of PGC‐1α when compared to young WT mice. Age‐dependent changes were also observed in morphology proteins, including higher levels of the fusion protein Mfn2 in both WT and PolG mice, and reduced levels of the fission protein Fis1, only in WT and not in PolG mice. These data suggest that alterations in the ratio of fusion to fission proteins may contribute to the aging phenotype that is exhibited in mtDNA mutator mice.
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