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.

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 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 In Vivo and Ex Vivo Evaluation of 1,3-Thiazolidine-2,4-Dione Derivatives as Euglycemic Agents

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Diana Alemán-González-Duhart ◽  
Samuel Álvarez-Almazán ◽  
Miguel Valdes ◽  
Feliciano Tamay-Cach ◽  
Jessica Elena Mendieta-Wejebe
Keyword(s):  
Antioxidant Activity ◽  
Ex Vivo ◽  
Peroxisome Proliferator ◽  
Oral Toxicity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tissue Samples ◽  
Design Synthesis ◽  
Antioxidant Agents ◽  
Male Wistar Rats

Thiazolidinediones (TZDs), used to treat type 2 diabetes mellitus, act as full agonists of the peroxisome proliferator-activated receptor gamma. Unfortunately, they produce adverse effects, including weight gain, hepatic toxicity, and heart failure. Our group previously reported the design, synthesis, in silico evaluation, and acute oral toxicity test of two TZD derivatives, compounds 40 (C40) and 81 (C81), characterized as category 5 and 4, respectively, under the Globally Harmonized System. The aim of this study was to determine whether C40, C81, and a new compound, C4, act as euglycemic and antioxidant agents in male Wistar rats with streptozotocin-induced diabetes. The animals were randomly divided into six groups ( n = 7 ): the control, those with diabetes and untreated, and those with diabetes and treated with pioglitazone, C40, C81, or C4 (daily for 21 days). At the end of the experiment, tissue samples were collected to quantify the level of glucose, insulin, triglycerides, total cholesterol, and liver enzymes, as well as enzymatic and nonenzymatic antioxidant activity. C4, without a hypoglycemic effect, displayed the best antioxidant activity. Whereas C81 could only attenuate the elevated level of blood glucose, C40 generated euglycemia by the end of the treatment. All compounds produced a significant decrease in triglycerides.

scholarly journals An Increase in Murine Skeletal Muscle Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α (PGC-1α) mRNA in Response to Exercise Is Mediated by β-Adrenergic Receptor Activation

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3441-3448 ◽  
Author(s):  
Shinji Miura ◽  
Kentaro Kawanaka ◽  
Yuko Kai ◽  
Mayumi Tamura ◽  
Masahide Goto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Adrenergic Receptor ◽  
Ex Vivo ◽  
Specific Inhibitor ◽  
Receptor Activation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose ◽  
Exercise Induced

A single bout of exercise increases expression of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1α expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1α mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the β2-AR agonist clenbuterol, but not α-, β1-, or β3-AR agonists, increased PGC-1α mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1α mRNA expression in mice was inhibited by pretreatment with the β-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to β2-AR agonist, but not α-, β1-, and β3-AR agonist, led to an increase in levels of PGC-1α mRNA. Injection of β2-AR agonist did not increase PGC-1α mRNA expression in β1-, β2-, and β3-AR knockout mice (β-less mice). PGC-1α mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1α mRNA was inhibited by approximately 70% by propranolol or the β2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1α mRNA in β-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1α expression in skeletal muscle by exercise is mediated, at least in part, by β-ARs activation. Among ARs, β2-AR may mediate an increase in PGC-1α by exercise.

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 Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor α (PPARα)

2002 ◽  
Vol 366 (3) ◽  
pp. 839-846 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Geoffrey F. GIBBONS ◽  
Mary C. SUGDEN
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Skeletal Muscles ◽  
Pyruvate Dehydrogenase Kinase ◽  
Glucose Disposal ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anterior Tibialis

In insulin deficiency, increased lipid delivery and oxidation suppress skeletal-muscle glucose oxidation by inhibiting pyruvate dehydrogenase complex (PDC) activity via enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4, which phosphorylates (and inactivates) PDC. Signalling via peroxisome-proliferator-activated receptor α (PPARα) is an important component of the mechanism enhancing hepatic and renal PDK4 protein expression. Activation of PPARα in gastrocnemius, a predominantly fast glycolytic (FG) muscle, also increases PDK4 expression, an effect that, if extended to all muscles, would be predicted to drastically restrict whole-body glucose disposal. Paradoxically, chronic activation of PPARα by WY14,643 treatment improves glucose utilization by muscles of insulin-resistant high-fat-fed rats. In the resting state, oxidative skeletal muscles are quantitatively more important for glucose disposal than FG muscles. We evaluated the participation of PPARα in regulating PDK4 protein expression in slow oxidative (SO) skeletal muscle (soleus) and fast oxidative-glycolytic (FOG) skeletal muscle (anterior tibialis) containing a high proportion of oxidative fibres. In the fed state, acute (24h) activation of PPARα by WY14,643 in vivo failed to modify PDK4 protein expression in soleus, but modestly enhanced PDK4 protein expression in anterior tibialis. Starvation enhanced PDK4 protein expression in both muscles, with the greater response in anterior tibialis. WY14,643 treatment in vivo during starvation did not further enhance upregulation of PDK4 protein expression in either muscle type. Enhanced PDK4 protein expression after starvation was retained in SO and FOG skeletal muscles of PPARα-deficient mice. Our data indicate that PDK4 protein expression in oxidative skeletal muscle is regulated by a lipid-dependent mechanism that is not obligatorily dependent on signalling via PPARα.

Human skeletal muscle PPARα expression correlates with fat metabolism gene expression but not BMI or insulin sensitivity

2004 ◽  
Vol 286 (2) ◽  
pp. E168-E175 ◽  
Author(s):  
Junlong Zhang ◽  
D. I. W. Phillips ◽  
Chunli Wang ◽  
Christopher D. Byrne
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Few Data

Peroxisome proliferator-activated receptor-α (PPARα) is a key regulator of fatty acid oxidation in skeletal muscle, but few data exist from humans in vivo. To investigate whether insulin sensitivity in skeletal muscle and body mass index (BMI) were associated with skeletal muscle expression of PPARα and with important genes regulating lipid metabolism in humans in vivo, we undertook hyperinsulinemic-euglycemic clamps and measured PPARα mRNA levels and mRNA levels of lipid regulating PPARα response genes in skeletal muscle biopsies. mRNA levels were measured in 16 men, using a novel highly sensitive and specific medium throughput quantitative competitive PCR that allows reproducible measurement of multiple candidate mRNAs simultaneously. mRNA levels of PPARα were positively correlated with mRNA levels of CD36 ( r = 0.77, P = 0.001), lipoprotein lipase ( r = 0.54, P = 0.024), muscle-type carnitine palmitoyltransferase-I ( r = 0.54, P = 0.024), uncoupling protein-2 ( r = 0.63, P = 0.008), and uncoupling protein-3 ( r = 0.53, P = 0.026), but not with measures of insulin sensitivity, BMI, or GLUT4, which plays an important role in insulin-mediated glucose uptake. Thus our data suggest that in humans skeletal muscle PPARα expression and genes regulating lipid metabolism are tightly linked, but there was no association between both insulin sensitivity and BMI with PPARα expression in skeletal muscle.

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