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• Research Paper Volume 14, Issue 3 pp 1157-1185

  Improved impedance to maladaptation and enhanced VCAM-1 upregulation with resistance-type training in the long-lived Snell dwarf (Pit1^dw/dw) mouse

  Relevance score: 7.6818542

  Erik P. Rader, Marshall A. Naimo, James Ensey, Brent A. Baker

  Keywords: skeletal muscle, stretch-shortening contractions, plantarflexor muscles

  Published in Aging on February 3, 2022

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  Snell dwarf mice with the Pit1^dw/dw mutation are deficient in growth hormone, prolactin, and thyroid stimulating hormone and exhibit >40% lifespan extension. This longevity is accompanied by compromised muscular performance. However, research regarding young (3-month-old) Snell dwarf mice demonstrate exceptional responsivity to resistance-type training especially in terms of a shifted fiber type distribution and increased protein levels of vascular cell adhesion molecule-1 (VCAM-1), a possible mediator of such remodeling. In the present study, we investigated whether this responsiveness persists at 12 months of age. Unlike 12-month-old control mice, age-matched Snell dwarf mice remained resistant to training-induced maladaptive decreases in performance and muscle mass. This was accompanied by retainment of the remodeling capacity in muscles of Snell dwarf mice to increase VCAM-1 protein levels and a shift in myosin heavy chain (MHC) isoform distribution with training. Even decreasing training frequency for control mice, an alteration which protected muscles from maladaptation at 12 months of age, did not result in the overt remodeling observed for Snell dwarf mice. The results demonstrate a distinct remodeling response to resistance-type exercise operative in the context of the Pit1^dw/dw mutation of long-lived Snell dwarf mice.

• Editorial Volume 11, Issue 8 pp 2183-2184

  Is obesity a risk factor for skeletal muscle ageing?

  Relevance score: 7.027758

  Cameron Hill, Jason Tallis

  Keywords: isolated muscles, obesity, sarcopenic obesity, power, force, muscle quality

  Published in Aging on April 29, 2019

  

  Impact of obesity in old age on skeletal muscle function. Excessive adiposity in old age causes a significant reduction in contractile performance in humans (A). Less is known about how obesity in old age affects muscle quality (force or power relative to muscle mass), so usage of an isolated muscle model can provide information about the contractile performance of isolated respiratory (B) and locomotor (C) skeletal muscles, otherwise difficult to examine in vivo (observations from Hill et al., 2019). Whilst the studies of in vivo and in vitro muscle performance do not reciprocate one another, the overall consequence of the altered contractile performance of old obese skeletal muscles is a poorer quality of life. ADL, Activities of daily living. Images from BioRender.

  
  
  

• Research Paper Volume 4, Issue 7 pp 456-461

  An autoregulatory loop reverts the mechanosensitive Sirt1 induction by EGR1 in skeletal muscle cells

  Relevance score: 8.087676

  Patricia S. Pardo, Aladin M. Boriek

  Keywords: Mechanotransduction, oxidative stress, skeletal muscles, Sirt1

  Published in Aging on July 18, 2012

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  Muscle contraction is associated with the production of reactive oxygen species (ROS). Mechanisms of ROS scavenging are fundamental to avoid muscle damage. We had previously discovered a stretch-induced genetic program in myotubes that triggers an antioxidant defense. At the core of this mechanism, transcriptional activation of SIRT1 by the early growth response protein EGR1 results in increased MnSOD activity through the activation of Sod2 by SIRT1/FOXO pathway. In this report, we show experimental evidence that; a) EGR1 and SIRT1 proteins physically interact at the time of maximal Sirt1 induction, b) SIRT1 has a negative effect on the activation of the Sirt1 promoter by EGR1. Thus, the interaction between EGR1 and SIRT1 describes an autoregulatory loop that shuts down the stretch-induced Sirt1 expression.

  

  (a) C2C12 myotubes were cultured on 7 FlexCell plates, 6 plates were subjected to 30 min stretch while a set of myotubes was kept without stretch (ns), stretched myotubes were harvested at different times after stretch from 0 to 6 hours. 80 μg of total protein from each sample and molecular weight markers (MW) were subjected to SDS-PAGE and Western blot with antibodies against SIRT1, EGR1 and tubulin. Molecular weight markers positions are displayed on the left of the western blot scan images. (b) SIRT1 RNA content was determined by RT-real time PCR in stretched and non-stretched myotubes by RT-real time PCR and fold stimulation represents the stretched/non-stretched SIRT1 RNA content ratios (*indicates statistical significant difference from non-stretched) (c) Stably expressing FLAG-EGR1C2C12 cells (C2C12 12.4 clone) were plated in flexible bottomed plates and a set of cells were stretched (s) whereas another set was used as non-stretched controls (ns). Total proteins were obtained 3 hours after stretch; 0.5 mg of protein were incubated with protein A/G agarose beads loaded with a rabbit SIRT1 antibody or without antibody (mock); 50μg of total protein (input) and mock and SIRT1 immunoprecipitates were subjected to SDS-PAGE and Western blot with a monoclonal anti-FLAG M2 peroxidase conjugated antibody (Sigma-Aldrich). (d) Total proteins (0.4 mg) from non-stretched myotubes (ns), myotubes subjected to 30 min stretch and harvested immediately (s0) or 3 hours after (s3) were immunoprecipitated with anti-EGR1, 75 μg of total protein (input) and immunoprecipitates from each sample were analyzed by Western blot with a mouse monoclonal anti-SIRT1 (Sigma-Aldrich) or a mouse monoclonal anti-acetyl lysine (Upstate). The numbers below each lane represent the estimate ratio of acetylated EGR1.total EGR1 obtained by densitometric analysis of the films. (e) 0.75 mg of total protein from C2C12 12.4 cells transfected with pYE-Sir2 or pYE-Sir2 (H/Y) were incubated overnight without (mock) or with a rabbit polyclonal anti-acetyl lysine antibody and immunoprecipitated with A/G agarose beads; 80ug of total protein and total immunoprecipitates were subjected to Western blot with anti-FLAG M2 peroxidase, images of the film exposed for 1 min (right) or 10 sec(left) are shown.

  
  
  

  

  (a) ChIP assays were performed with EGR1(▭) and SIRT1 (▬) antibodies on non-stretched myotubes (ns), myotubes subjected to 30 min stretch and harvested immediately (s0) or 3 hours after (s3), immunoprecipitated DNA was analyzed by real time PCR with primers for the EGR1 binding sites and promoter occupancy was estimated as described in Methods. * and # indicates statistical significant difference from ns or s0, respectively. (b) C2C12 myoblasts grown on 24 well plates were transfected with the Sirt1 promoter reporter (0.1 μg/well) in the absence or presence of pcDNA-EGR1 and/or pcDNA-SIRT1 (0.2 μg/well); pcDNA was incorporated in the DNA mixtures to complete 0.5 μg/well and nicotinamide (NAM) to a 10 mM final concentration was added to the media when indicated. Luciferase activity was determined 24 hours after transfection with Dual Glo luciferase (Promega), * and # means statistical significant difference from empty vector or EGR1, respectively.

  
  
  

  

  The scheme summarizes the stretch-induced pathway that allows ROS scavenging in response to mechanical stimuli. As previously described, stretch–dependent transcriptional activation of Sirt1 by EGR1 activates the Sod2 gene by stimulating FOXO binding to the Sod2 promoter leading to lowering ROS content to its basal levels [6]. The interaction between EGR1 and SIRT1 prevents EGR1 binding to the Sirt1 promoter triggering an autoregularoty loop that turns down SIRT1 expression from the stretch-induced to basal levels.

  
  
  

• Research Paper Volume 4, Issue 3 pp 206-223

  dSir2 deficiency in the fatbody, but not muscles, affects systemic insulin signaling, fat mobilization and starvation survival in flies

  Relevance score: 6.44165

  Kushal Kr. Banerjee, Champakali Ayyub, Samudra Sengupta, Ullas Kolthur-Seetharam

  Keywords: Sir2, fat metabolism, starvation, survival, fatbody, muscles, insulin signaling

  Published in Aging on March 10, 2012

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  Sir2 is an evolutionarily conserved NAD⁺ dependent protein. Although, SIRT1 has been implicated to be a key regulator of fat and glucose metabolism in mammals, the role of Sir2 in regulating organismal physiology, in invertebrates, is unclear. Drosophila has been used to study evolutionarily conserved nutrient sensing mechanisms, however, the molecular and metabolic pathways downstream to Sir2 (dSir2) are poorly understood. Here, we have knocked down endogenous dSir2 in a tissue specific manner using gene-switch gal4 drivers. Knockdown of dSir2 in the adult fatbody leads to deregulated fat metabolism involving altered expression of key metabolic genes. Our results highlight the role of dSir2 in mobilizing fat reserves and demonstrate that its functions in the adult fatbody are crucial for starvation survival. Further, dSir2 knockdown in the fatbody affects dilp5 (insulin-like-peptide) expression, and mediates systemic effects of insulin signaling. This report delineates the functions of dSir2 in the fatbody and muscles with systemic consequences on fat metabolism and insulin signaling. In conclusion, these findings highlight the central role that fatbody dSir2 plays in linking metabolism to organismal physiology and its importance for survival.

  

  (A) Starvation survival of dSir2 mutants (Sir2^2A.7.11) (p < 0.001) and (B) whole body dSir2^RNAi (+ RU486) (p < 0.001), with respective controls (n = 60). (C)dSir2 transcript levels increase in response to 48-hours starvation in control (- RU486) but not in whole body dSir2^RNAi(+ RU486) flies (n = 8/24). (D) Increase in dSir2 protein levels in control flies in response to 48-hours starvation. (E) Increase in NAD⁺ levels in response to 48-hours starvation in control flies (n = 36). 200 μM RU486 was used to knockdown dSir2 expression inpSw-tub-gal4>dSir2^RNAi flies. Log Rank was used to plot survival curves and Mantel-Cox test was used for statistical analysis. Student's t-test and ANOVA were used to analyze statistical significance of the data (*, p < 0.05; **, p < 0.01; ***, p < 0.001 or mentioned otherwise).

  
  
  

  

  (A) Total body triglyceride (TAG) in dSir2 mutants (Sir2^2A.7.11) and whole body dSir2^RNAi (+ RU486) flies, with respective controls (n = 36). (B) Oil-Red O staining of fatbodies from control and Sir2^2A.7.11. (C) Relative expression of fat metabolism genes lipase-3 (lip3), brummer (brmm), mitochondrial acyl carrier protein (mtACP), medium chain acyl CoA dehydrogenase (mcad), aceto acetyl CoA thiolase (ACoT), long chain acyl CoA dehydrogenase (lcad), acetyl CoA carboxylase (ACC), fatty acid synthase (fas) and diacyl glycerol synthase (dDAG) (n = 24). 200 μM RU486 was used to knockdown dSir2 expression in pSw-tub-gal4>dSir2^RNAi flies. Student's t-test was used to analyze statistical significance of the data (*, p < 0.05; **, p < 0.01; ***, p < 0.001 or mentioned otherwise).

  
  
  

  

  (A) RT-PCR to show knockdown of dSir2 in the fatbody (FB) of fatbody dSir2^RNAiand body wall with muscles (BWM) of muscle dSir2^RNAi, with respective controls (n = 24). (B-C) Total body triglyceride levels in (B) fatbody dSir2^RNAi flies and (C) muscles dSir2^RNAi flies (n = 36). (D) Triglyceride levels in the isolated fatbody of fatbody dSir2^RNAi flies (n = 60). (E) Relative expression of fat metabolism genes lipase-3 (lip3), brummer (brmm), medium chain acyl CoA dehydrogenase (mcad), long chain acyl CoA dehydrogenase (lcad) and fatty acid synthase (fas) in fatbody isolated from fatbody dSir2^RNAi flies (n = 24). 200 μM RU486 was used to knockdown dSir2 expression pSw-S₁106-gal4>dSir2^RNAi and pSw-MHC-gal4> dSir2^RNAi flies. Student's t-test was used to analyze statistical significance of the data (*, p < 0.05; **, p < 0.01; ***, p < 0.001 or mentioned otherwise).

  
  
  

  

  (A and B) Starvation survival in (A) fatbody dSir2 knockdown flies (p < 0.001) and (B) muscle dSir2 knockdown flies (non-significant, ns)(n = 60). 200 μM RU486 was used to knockdown dSir2 expression pSw-S₁106-gal4>dSir2^RNAi and pSw-MHC-gal4> dSir2^RNAi flies. Log Rank was used to plot survival curves and Mantel-Cox test was used for statistical analysis. (C-D) Total body triglyceride levels in fed and starved conditions in (C) whole bodydSir2^RNAiflies, with respective controls (n = 36) and (D) fatbody dSir2^RNAi (n = 36). Relative expression of fat metabolism genes (E) lipase-3 (lip3), (F) brummer (brmm), (G) medium chain acyl CoA dehydrogenase (mcad), (H) fatty acid synthase (fas) in fatbody dSir2 knockdown flies under fed and starved conditions (n = 24). 200 μM RU486 was used to knockdown dSir2 expression pSw-S₁106-gal4>dSir2^RNAi and pSw-MHC-gal4> dSir2^RNAi flies. ANOVA was used to analyze statistical significance of the data (*, p < 0.05; **, p < 0.01; ***, p < 0.001 or mentioned otherwise).

  
  
  

  

  (A-C) Relative dilp5 levels in the heads of (A) whole body dSir2^RNAi (B) fatbody dSir2^RNAi and (C) muscle dSir2^RNAi flies, with respective controls, under fed and starved conditions (n = 24). Relative expression of (D) dInR and (E) d4eBP in fatbody dSir2^RNAi flies under fed and starved conditions (n = 24). (F) Starvation survival of fatbody dSir2 knockdown (pSw-S₁106-gal4>+/+;dSir2^RNAi + RU486) and control (pSw-S₁106-gal4>+/+;dSir2^RNAi - RU486) flies, fatbody dSir2 knockdown in chico heterozygote flies (pSw-S₁106-gal4>ch^+/-; dSir2^RNAi + RU486) and (pSw-S₁106-gal4>ch^+/-; dSir2^RNAi- RU486) (statistical significance indicated in supplementary figure 9) (n = 60).200 μM RU486 was used to knockdown dSir2 expression. Log Rank was used to plot survival curves and Mantel-Cox test was used for statistical analysis. Student's t-test and ANOVA were used to analyze statistical significance of the data (*, p < 0.05; **, p < 0.01; ***, p < 0.001 or mentioned otherwise).

  
  
  

• Research Paper pp undefined-undefined

  Aberrant expression of thyroidal hormone receptor α exasperating mitochondrial dysfunction induced sarcopenia in aged mice

  Relevance score: 5.903216

  Yunlu Sheng, Xiaoxia Zhu, Lijun Wei, Yuxin Zou, Xinyu Qi, Runqing Shi, Wenli Xu, Xiaodong Wang, Guoxian Ding, Yu Duan

  Keywords: thyroid hormone receptor α, mitochondrial dysfunction, mitophagy, skeletal muscles, aging mice

  Published in Aging on Invalid Date

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  Disrupted mitochondrial dynamics and mitophagy contribute to functional deterioration of skeletal muscle (SM) during aging, but the regulatory mechanisms are poorly understood. Our previous study demonstrated that the expression of thyroid hormone receptor α (TRα) decreased significantly in aged mice, suggesting that the alteration of thyroidal elements, especially the decreased TRα, might attenuate local THs action thus to cause the degeneration of SM with aging, while the underlying mechanism remains to be further explored. In this study, decreased expression of myogenic regulators Myf5, MyoD1, mitophagy markers Pink1, LC3II/I, p62, as well as mitochondrial dynamic factors Mfn1 and Opa1, accompanied by increased reactive oxygen species (ROS), showed concomitant changes with reduced TRα expression in aged mice. Further TRα loss- and gain- of function studies in C2C12 revealed that silencing of TRα not only down-regulated the expression of above-mentioned myogenic regulators, mitophagy markers and mitochondrial dynamic factors, but also led to a significant decrease in mitochondrial activity and maximum respiratory capacity, as well as more mitochondrial ROS and damaged mitochondria. Notedly, overexpression of TRα could up-regulate the expression of those myogenic regulators, mitophagy markers and mitochondrial dynamic factors, meanwhile also led to an increase in mitochondrial activity and number. These results confirmed that TRα could concertedly regulate mitochondrial dynamics, autophagy, and activity, and myogenic regulators rhythmically altered with TRα expression. Summarily, these results suggested that the decline of TRα might cause the degeneration of SM with aging by regulating mitochondrial dynamics, mitophagy and myogenesis.