scholarly journals Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nandini Ghosh ◽  
Amitava Das ◽  
Nirupam Biswas ◽  
Surya Gnyawali ◽  
Kanhaiya Singh ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
C2c12 Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Urolithin A ◽  
Silent Information Regulator 1 ◽  
Angiogenic Markers ◽  
Pathway Inhibition

AbstractUrolithin A (UA) is a natural compound that is known to improve muscle function. In this work we sought to evaluate the effect of UA on muscle angiogenesis and identify the underlying molecular mechanisms. C57BL/6 mice were administered with UA (10 mg/body weight) for 12–16 weeks. ATP levels and NAD+ levels were measured using in vivo 31P NMR and HPLC, respectively. UA significantly increased ATP and NAD+ levels in mice skeletal muscle. Unbiased transcriptomics analysis followed by Ingenuity Pathway Analysis (IPA) revealed upregulation of angiogenic pathways upon UA supplementation in murine muscle. The expression of the differentially regulated genes were validated using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Angiogenic markers such as VEGFA and CDH5 which were blunted in skeletal muscles of 28 week old mice were found to be upregulated upon UA supplementation. Such augmentation of skeletal muscle vascularization was found to be bolstered via Silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α) pathway. Inhibition of SIRT1 by selisistat EX527 blunted UA-induced angiogenic markers in C2C12 cells. Thus this work provides maiden evidence demonstrating that UA supplementation bolsters skeletal muscle ATP and NAD+ levels causing upregulated angiogenic pathways via a SIRT1-PGC-1α pathway.

scholarly journals Growth hormone controls lipolysis by regulation of FSP27 expression

2018 ◽  
Vol 239 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Rita Sharma ◽  
Quyen Luong ◽  
Vishva M Sharma ◽  
Mitchell Harberson ◽  
Brian Harper ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Specific Protein ◽  
Negative Regulator ◽  
Gamma Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

scholarly journals Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells

2006 ◽  
Vol 282 (7) ◽  
pp. 4417-4426 ◽  
Author(s):  
Cicerone Tudor ◽  
Jérôme N. Feige ◽  
Harikishore Pingali ◽  
Vidya Bhushan Lohray ◽  
Walter Wahli ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Molecular Mechanisms ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Living Cells ◽  
Correlation Spectroscopy ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Chronic rosiglitazone treatment restores AMPKα2 activity in insulin-resistant rat skeletal muscle

2006 ◽  
Vol 290 (2) ◽  
pp. E251-E257 ◽  
Author(s):  
Sarah J. Lessard ◽  
Zhi-Ping Chen ◽  
Matthew J. Watt ◽  
Michael Hashem ◽  
Julianne J. Reid ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Zucker Rats ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Palmitate Oxidation ◽  
Insulin Resistant ◽  
Obese Zucker Rats

Rosiglitazone (RSG) is an insulin-sensitizing thiazolidinedione (TZD) that exerts peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent effects. We tested the hypothesis that part of the insulin-sensitizing effect of RSG is mediated through the action of AMP-activated protein kinase (AMPK). First, we determined the effect of acute (30–60 min) incubation of L6 myotubes with RSG on AMPK regulation and palmitate oxidation. Compared with control (DMSO), 200 μM RSG increased ( P < 0.05) AMPKα1 activity and phosphorylation of AMPK (Thr172). In addition, acetyl-CoA carboxylase (Ser218) phosphorylation and palmitate oxidation were increased ( P < 0.05) in these cells. To investigate the effects of chronic RSG treatment on AMPK regulation in skeletal muscle in vivo, obese Zucker rats were randomly allocated into two experimental groups: control and RSG. Lean Zucker rats were treated with vehicle and acted as a control group for obese Zucker rats. Rats were dosed daily for 6 wk with either vehicle (0.5% carboxymethylcellulose, 100 μl/100 g body mass), or 3 mg/kg RSG. AMPKα1 activity was similar in muscle from lean and obese animals and was unaffected by RSG treatment. AMPKα2 activity was ∼25% lower in obese vs. lean animals ( P < 0.05) but was normalized to control values after RSG treatment. ACC phosphorylation was decreased with obesity ( P < 0.05) but restored to the level of lean controls with RSG treatment. Our data demonstrate that RSG restores AMPK signaling in skeletal muscle of insulin-resistant obese Zucker rats.

scholarly journals Musclin is an activity-stimulated myokine that enhances physical endurance

2015 ◽  
Vol 112 (52) ◽  
pp. 16042-16047 ◽  
Author(s):  
Ekaterina Subbotina ◽  
Ana Sierra ◽  
Zhiyong Zhu ◽  
Zhan Gao ◽  
Siva Rama Krishna Koganti ◽  
...  
Keyword(s):  
Exercise Capacity ◽  
Exercise Tolerance ◽  
Skeletal Muscles ◽  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Guanosine Monophosphate ◽  
Physical Endurance ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Exercise remains the most effective way to promote physical and metabolic wellbeing, but molecular mechanisms underlying exercise tolerance and its plasticity are only partially understood. In this study we identify musclin—a peptide with high homology to natriuretic peptides (NP)—as an exercise-responsive myokine that acts to enhance exercise capacity in mice. We use human primary myoblast culture and in vivo murine models to establish that the activity-related production of musclin is driven by Ca2+-dependent activation of Akt1 and the release of musclin-encoding gene (Ostn) transcription from forkhead box O1 transcription factor inhibition. Disruption of Ostn and elimination of musclin secretion in mice results in reduced exercise tolerance that can be rescued by treatment with recombinant musclin. Reduced exercise capacity in mice with disrupted musclin signaling is associated with a trend toward lower levels of plasma atrial NP (ANP) and significantly smaller levels of cyclic guanosine monophosphate (cGMP) and peroxisome proliferator-activated receptor gamma coactivator 1-α in skeletal muscles after exposure to exercise. Furthermore, in agreement with the established musclin ability to interact with NP clearance receptors, but not with NP guanyl cyclase-coupled signaling receptors, we demonstrate that musclin enhances cGMP production in cultured myoblasts only when applied together with ANP. Elimination of the activity-related musclin-dependent boost of ANP/cGMP signaling results in significantly lower maximum aerobic capacity, mitochondrial protein content, respiratory complex protein expression, and succinate dehydrogenase activity in skeletal muscles. Together, these data indicate that musclin enhances physical endurance by promoting mitochondrial biogenesis.

scholarly journals Metabolic regulation of exercise-induced angiogenesis

2019 ◽  
Vol 1 (1) ◽  
pp. H1-H8 ◽  
Author(s):  
Tatiane Gorski ◽  
Katrien De Bock
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Metabolic Reprogramming ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Valuable Insight ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced

Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. In skeletal muscle, angiogenesis can occur via sprouting and splitting angiogenesis and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation of Vegf expression and increased muscle capillary density. While ECs are highly glycolytic and change their metabolism during sprouting angiogenesis in development and disease, a similar role for EC metabolism in exercise-induced angiogenesis in skeletal muscle remains to be elucidated. Nonetheless, recent studies have illustrated the importance of endothelial hydrogen sulfide and sirtuin 1 (SIRT1) activity for exercise-induced angiogenesis, suggesting that EC metabolic reprogramming may be fundamental in this process. We hypothesize that the exercise-induced angiogenic response can also be modulated by metabolic crosstalk between muscle and the endothelium. Defining the underlying molecular mechanisms responsible for skeletal muscle angiogenesis in response to exercise will yield valuable insight into metabolic regulation as well as the determinants of exercise performance.

scholarly journals Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type

2012 ◽  
Vol 302 (1) ◽  
pp. C88-C99 ◽  
Author(s):  
Serge Summermatter ◽  
Raphael Thurnheer ◽  
Gesa Santos ◽  
Barbara Mosca ◽  
Oliver Baum ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Calcium Release ◽  
Ex Vivo ◽  
Fiber Type ◽  
Force Production ◽  
Calcium Handling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Calcium Clearance

Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1α overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.

scholarly journals The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2623
Author(s):  
Giuseppina Augimeri ◽  
Cinzia Giordano ◽  
Luca Gelsomino ◽  
Pierluigi Plastina ◽  
Ines Barone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Basic Research ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Natural And Synthetic

Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression, and metastasis. Over the last decade, much research has focused on the potential of natural agonists for PPARγ including fatty acids and prostanoids that act as weak ligands compared to the strong and synthetic PPARγ agonists such as thiazolidinedione drugs. Both natural and synthetic compounds have been implicated in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer focusing on the underlying cellular and molecular mechanisms involved in the regulation of cell proliferation, cell cycle, and cell death, in the modulation of motility and invasion as well as in the cross-talk with other different signaling pathways. Besides, we also provide an overview of the in vivo breast cancer models and clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer.

scholarly journals Improved skeletal muscle Ca2+ regulation in vivo following contractions in mice overexpressing PGC-1α

2017 ◽  
Vol 312 (6) ◽  
pp. R1017-R1028 ◽  
Author(s):  
Hiroaki Eshima ◽  
Shinji Miura ◽  
Nanami Senoo ◽  
Koji Hatakeyama ◽  
David C. Poole ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Tibialis Anterior Muscle ◽  
Recovery Period ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
S 100 ◽  
Intracellular Ca ◽  
Related Proteins

In skeletal muscle, resting intracellular Ca2+ concentration ([Ca2+]i) homeostasis is exquisitely regulated by Ca2+ transport across the sarcolemmal, mitochondrial, and sarcoplasmic reticulum (SR) membranes. Of these three systems, the relative importance of the mitochondria in [Ca2+]i regulation remains poorly understood in in vivo skeletal muscle. We tested the hypothesis that the capacity for Ca2+ uptake by mitochondria is a primary factor in determining [Ca2+]i regulation in muscle at rest and following contractions. Tibialis anterior muscle of anesthetized peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-overexpressing (OE, increased mitochondria model) and wild-type (WT) littermate mice was exteriorized in vivo and loaded with the fluorescent probe fura 2-AM, and Rhod 2-AM Ca2+ buffering and mitochondrial [Ca2+] were evaluated at rest and during recovery from fatiguing tetanic contractions induced by electrical stimulation (120 s, 100 Hz). In addition, the effects of pharmacological inhibition of SR (thapsigargin) and mitochondrial [carbonyl cyanide- 4-(trifluoromethoxy) phenylhydrazone (FCCP)] function were examined at rest. [Ca2+]i in WT remained elevated for the entire postcontraction recovery period (+6 ± 1% at 450 s), but in PGC-1α OE [Ca2+]i returned to resting baseline within 150 s. Thapsigargin immediately and substantially increased resting [Ca2+]i in WT, whereas in PGC-1α OE this effect was delayed and markedly diminished (WT, +12 ± 3; PGC-1α OE, +1 ± 2% at 600 s after thapsigargin treatment, P < 0.05). FCCP abolished this improvement of [Ca2+]i regulation in PGC-1α OE. Mitochondrial [Ca2+] accumulation was observed in PGC-1α OE following contractions and thapsigargin treatment. In the SR, PGC-1α OE downregulated SR Ca2+-ATPase 1 (Ca2+ uptake) and parvalbumin (Ca2+ buffering) protein levels, whereas mitochondrial Ca2+ uptake-related proteins (Mfn1, Mfn2, and mitochondrial Ca2+ uniporter) were upregulated. These data demonstrate a heretofore unappreciated role for skeletal muscle mitochondria in [Ca2+]i regulation in vivo following fatiguing tetanic contractions and at rest.

scholarly journals MEF2 as upstream regulator of the transcriptome signature in human skeletal muscle during unloading

2018 ◽  
Vol 315 (4) ◽  
pp. R799-R809 ◽  
Author(s):  
Eric Rullman ◽  
Rodrigo Fernandez-Gonzalo ◽  
Igor B. Mekjavić ◽  
Thomas Gustafsson ◽  
Ola Eiken
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Vastus Lateralis ◽  
Bed Rest ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Gene Expression ◽  
Transcriptional Signature ◽  
Upstream Regulator ◽  
Transcriptome Signature

Our understanding of skeletal muscle structural and functional alterations during unloading has increased in recent decades, yet the molecular mechanisms underpinning these changes have only started to be unraveled. The purpose of the current investigation was to assess changes in skeletal muscle gene expression after 21 days of bed rest, with a particular focus on predicting upstream regulators of muscle disuse. Additionally, the association between differential microRNA expression and the transcriptome signature of bed rest were investigated. mRNAs from musculus vastus lateralis biopsies obtained from 12 men before and after the bed rest were analyzed using a microarray. There were 54 significantly upregulated probesets after bed rest, whereas 103 probesets were downregulated (false discovery rate 10%; fold-change cutoff ≥1.5). Among the upregulated genes, transcripts related to denervation-induced alterations in skeletal muscle were identified, e.g., acetylcholine receptor subunit delta and perinatal myosin. The most downregulated transcripts were functionally enriched for mitochondrial genes and genes involved in mitochondrial biogenesis, followed by a large number of contractile fiber components. Upstream regulator analysis identified a robust inhibition of the myocyte enhancer factor-2 (MEF2) family, in particular MEF2C, which was suggested to act upstream of several key downregulated genes, most notably peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α)/peroxisome proliferator-activated receptors (PPARs) and CRSP3. Only a few microRNAs were identified as playing a role in the overall transcriptome picture induced by sustained bed rest. Our results suggest that the MEF2 family is a key regulator underlying the transcriptional signature of bed rest and, hence, ultimately also skeletal muscle alterations induced by systemic unloading in humans.

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