SIRT1 is the first member of the Sirtuin protein family to be discovered. SIRT1is a longevity associated protein; activation of SIRT1 in mice was associated with a delay in the onset of many aging-related diseases, including osteoporosis [53]. Enzymes associated with SIRT1 are histone acetylation enzymes and, therefore, can regulate several molecules including NF-κB, enabling SIRT1 to regulate inflammation [54]. It has been reported that resveratrol-mediated SIRT1 activation can inhibit the NF-kB signalling pathway promoting osteoblasts differentiation [35, 39, 48]. Additionally, resveratrol can elicit a SIRT1-dependent inhibition of osteoclastogenesis [55]. Human adult retinal pigment epithelial (RPE) cells pre-treated with the SIRT1 activator SRT1720 showed abrogation of IL-8, IL-6 and MMP-9 expression [56]. The anti-apoptotic and anti-oxidant effects of resveratrol were abolished by SIRT1 knockdown in C2C12 myoblast cells; suggesting that SIRT1 is pivotal in mediating resveratrol-induced cell protecting effects [57]. SIRT1 siRNA blocked the anti-osteoporotic effect of resveratrol in ovariectomized rat model strengthening the assumption that resveratrol exerts its anti-osteoporotic action via SIRT1-NF-κB pathway [27, 35]. FoxO1, a member of the Forkhead box O family of proteins, is the most abundant isoform in osteoblasts. Accordingly, FoxO1 is thought to control bone formation through osteoblasts proliferation and differentiation, and redox balance [58]. FoxO1 can counteract the generation of ROS by over-expression of the antioxidant enzymes such as glutathione peroxidise and superoxide dismutase [59]. It has been reported that in hematopoietic stem cells FoxO1 reduces ROS by up-regulating the expression of anti-oxidant enzymes, whereas FoxO1 deletion led to an increase in osteoclast progenitors in the bone marrow [60]. FoxO1 is a target for SIRT1; SIRT1 appears to shift the FoxO1-dependent response towards the antioxidant activity and redox balance [57]. Receptor activator of nuclear factor-κB (RANK) is a member of the tumor necrosis factor family expressed by osteoclasts. The final common pathway in the regulation of bone resorption involves the interaction of RANK with its ligand (RANKL) [61]. Inhibiting RANKL significantly affects bone metabolism, and therefore, is a reasonable therapeutic strategy for the treatment of osteoporosis and other bone diseases characterized by increased bone turnover. OPG is the natural inhibitor of RANKL; Osteoporosis developed in OPG-deficient mice, while over-expression of OPG in mice inhibited osteoclastogenesis and improveded bone mass [62, 63]. Taken together, resveratrol seems to be able to shift the RANKL/OPG pathways toward osteobalstogenesis in age-dependent male osteoporosis.
PGC-1 (peroxisome-proliferator-activated receptor-γ coactivator-1) alpha is a potent transcriptional coactivator that coordinates the activation of numerous metabolic processes. Exercise strongly induces PGC-1alpha expression in muscle, and overexpression of PGC-1alpha in skeletal muscle activates mitochondrial oxidative metabolism and neovascularization, leading to markedly increased endurance. In light of these findings, PGC-1alpha has been proposed to protect from age-associated sarcopenia, bone loss, and whole-body metabolic dysfunction, although these findings have been controversial. We therefore comprehensively evaluated muscle and whole-body function and metabolism in 24-month-old transgenic mice that over-express PGC-1alpha in skeletal muscle. We find that the powerful effects of PGC-1alpha on promoting muscle oxidative capacity and protection from muscle fatigability persist in aged animals, although at the expense of muscle strength. However, skeletal muscle PGC-1alpha does not prevent bone loss and in fact accentuates it, nor does it have long-term benefit on whole-body metabolic composition or insulin sensitivity. Protection from sarcopenia is seen in male animals with overexpression of PGC-1alpha in skeletal muscle but not in female animals. In summary, muscle-specific expression of PGC-1alpha into old age has beneficial effects on muscle fatigability and may protect from sarcopenia in males, but does not improve whole-body metabolism and appears to worsen age-related trabecular bone loss.
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Metabolic homeostasis requires a complex network of transcriptional programs. PGC-1 (peroxisome-proliferator-activated receptor-γ coactivator-1) alpha is a potent transcriptional coactivator that regulates a large number of nuclear-encoded genes [1,2,3], which, in turn, modulate numerous metabolic processes. In most cells and tissues, PGC-1alpha drives activation of mitochondrial biogenesis. In addition, PGC-1alpha promotes brown fat differentiation and thermogenesis [4], hepatic gluconeogenesis [5], cardiac homeostasis [6], and axonal integrity in the brain [7].
To resolve these unanswered questions, we endeavored to comprehensively evaluate muscle and whole-body function and metabolism in 24-month-old, male and female mice over-expressing PGC-1alpha in skeletal muscle.
PGC-1alpha promotes mitochondrial biogenesis and angiogenesis in 24-month-old mice. a Quantitative real time-polymerase chain Rreaction (qPCR) of PGC1 coactivators and components of the electron transport chain on quadriceps isolated from 4-month or 24-month-old wildtype and MCKa mice. b Western blots for oxidative phosphorylation proteins in quadriceps (quantification is normalized to total protein using amido black). c CD31 immunohistochemistry on tibialis anterior cryosections. d qPCR for endothelial markers and angiogenesis genes in quadriceps. e Myofiber minimal Feret diameter in tibialis anterior cryosections [n = 5, 4, 5, 5 for WT (4 mo), MCKa (4 mo), WT (24 mo), and MCKa (24 mo) respectively]. *P
Elevation of PGC-1alpha in skeletal muscle has been previously suggested to protect from age-associated muscle mass loss (sarcopenia) but, as noted above, that report has been retracted [17]. We find that the mass of glycolytic extensor digitorum longus (EDL) and of oxidative soleus muscles (Fig. 2a) and the muscle cross-sectional areas in the same muscles (Fig. 2b) are higher in 24-month-old male MCKa animals, compared to littermate controls, indicating that indeed MCKa may protect from sarcopenia. It is important to note, however, that the MCKa mice also had higher bodyweights than littermate controls (Fig. 2c), suggesting that the larger muscle may not be a cell autonomous effect. Interestingly, we did not observe protection from sarcopenia (Fig. 2a, b) or higher body weights (Fig. 2c) in the aged females, suggesting a possible sexual dimorphic effect of skeletal muscle PGC-1alpha in the protection from sarcopenia. Finally, we observed no differences in central nucleation, or evidence of fibrosis, between age-matched MCKa and wildtype animals (Fig. 2d).
We next evaluated the functional effects of elevated PGC-1alpha on skeletal muscle in aged animals. We measured ex vivo both the contractile properties and the muscle fatigability of EDL and soleus muscles from 24-month-old mice. We found that in both males and females, EDL muscles from MCKa mice were markedly less fatigable than littermate controls (Fig. 3a and b), at the expense of significantly reduced twitch (Fig. 3a and c) and tetanic force (Fig. 3a and d). These differences were largely observed only in the fast-glycolytic EDL, whereas little difference was observed in the slow-oxidative soleus. PGC-1alpha thus can reduce fatigability in aged animals, as it does in young animals, though at the expense of muscle strength [12].
Skeletal muscle PGC-1alpha has little effect on whole-body metabolism in 24-month-old mice. a Glucose tolerance test (GTT) in male and female 24-month-old mice. Calculated AUC of GTTs. b Western blots for pAkt and Akt in quadriceps (quantification is normalized to loading control 14-3-3). c VO2, VCO2, and respiratory quotient (RER) in 24-month-old mice measured via Comprehensive Laboratory Animal Monitoring System (CLAMS). d Physical activity of 24-month-old mice measured via CLAMS [n = 5, 5 for 24-month-old WT and MCKa]. *P
The observed effects of PGC-1alpha on aged bone density would similarly be unfavorable in the clinic. Loss of trabecular bone, as was seen in the transgenic animals, is a hallmark of age-associated bone loss [19, 20]. Consistent with this, we find a strong trend of MCKa bones to early fracture under a bend test. These findings are at odds with those reported by the retracted 2009 paper [17]. Interestingly, cortical bone was increased in male MCKa mice. The reason for this increase is not clear, but may be related to their higher body weight, and the known relationship between lean mass and bone density. Alternatively, signals elicited from the transgenic muscle may have opposing effects on cortical and trabecular bone. For example, we find significant induction of mRNA expression of the PGC-1alpha target Fndc5 in aged MCKa animals, and injection of cleaved FNDC5 (aka irisin) in mice for 4 weeks has been shown to improve cortical bone mass [25], while conversely, genetic deletion of FNDC5 was recently reported to block osteolysis induced by ovariectomy, specifically affecting trabecular, and not cortical bone [21]. It may thus be that transgenic induction of PGC-1alpha in aged muscle promotes specifically trabecular bone loss via the induction and secretion of FNDC5, acting in either a paracrine or endocrine fashion. We cannot rule out, of course, that secreted factors other than FNDC5, or neural circuits, may contribute to the loss of bone density. It is also worth noting that individuals who regularly perform aerobic exercise, in whom FNDC5 is presumably induced, are in fact protected against bone loss, both trabecular and cortical. The MCKa mice thus likely only model a subset of the effects of aerobic exercise. 2ff7e9595c
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