Selective PPARδ agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study

2007 ◽  
Vol 293 (5) ◽  
pp. E1256-E1264 ◽  
Author(s):  
Beat M. Jucker ◽  
Dewen Yang ◽  
Warren M. Casey ◽  
Alan R. Olzinski ◽  
Carolyn Williams ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Uncoupling Protein ◽  
Coupling Efficiency ◽  
Atp Synthesis ◽  
Energy Coupling ◽  
Resonance Spectroscopy ◽  
High Dose ◽  
Muscle Lipid

Peroxisome proliferator-activated receptor-δ (PPARδ) activation results in upregulation of genes associated with skeletal muscle fatty acid oxidation and mitochondrial uncoupling. However, direct, noninvasive assessment of lipid metabolism and mitochondrial energy coupling in skeletal muscle following PPARδ stimulation has not been examined. Therefore, in this study we examined the response of a selective PPARδ agonist (GW610742X at 5 or 100 mg·kg−1·day−1 for 8 days) on skeletal-muscle lipid metabolism and mitochondrial coupling efficiency in rats by using in vivo magnetic resonance spectroscopy (MRS). There was a decrease in the intramyocellular lipid-to-total creatine ratio as assessed by in vivo 1H-MRS in soleus and tibialis anterior muscles by day 7 (reduced by 49 and 46%, respectively; P < 0.01) at the high dose. Following the 1H-MRS experiment ( day 8), [1-13C]glucose was administered to conscious rats to assess metabolism in the soleus muscle. The relative fat-vs.-carbohydrate oxidation rate increased in a dose-dependent manner (increased by 52 and 93% in the 5 and 100 mg·kg−1·day−1 groups, respectively; P < 0.05). In separate experiments where mitochondrial coupling was assessed in vivo ( day 7), 31P-MRS was used to measure hindlimb ATP synthesis and 13C-MRS was used to measure the hindlimb tricarboxylic acid cycle flux (Vtca). There was no alteration, at either dose, in mitochondrial coupling efficiency measured as the ratio of unidirectional ATP synthesis flux to Vtca. Soleus muscle GLUT4 expression was decreased by twofold, whereas pyruvate dehydrogenase kinase 4, carnitine palmitoyl transferase 1a, and uncoupling protein 2 and 3 expression was increased by two- to threefold at the high dose ( P < 0.05). In summary, these are the first noninvasive measurements illustrating a selective PPARδ-mediated decrease in muscle lipid content that was consistent with a shift in metabolic substrate utilization from carbohydrate to lipid. However, the mitochondrial-energy coupling efficiency was not altered in the presence of increased uncoupling protein expression.

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.

Skeletal muscle lipid metabolism studied by advanced magnetic resonance spectroscopy

2012 ◽  
Vol 65 ◽  
pp. 66-76 ◽  
Author(s):  
Arunima Pola ◽  
Suresh Anand Sadananthan ◽  
Jadegoud Yaligar ◽  
Vijayasarathi Nagarajan ◽  
Weiping Han ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
Muscle Lipid ◽  
Skeletal Muscle Lipid

Skeletal muscle mitochondrial function studied by kinetic analysis of postexercise phosphocreatine resynthesis

1995 ◽  
Vol 78 (6) ◽  
pp. 2131-2139 ◽  
Author(s):  
C. H. Thompson ◽  
G. J. Kemp ◽  
A. L. Sanderson ◽  
G. K. Radda
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Maximum Rate ◽  
Atp Synthesis ◽  
Resonance Spectroscopy ◽  
Mitochondrial Regulation ◽  
Cardiac Infarction ◽  
Theoretical Approaches

To investigate mitochondrial regulation and its response to a defect in oxidative metabolism, we used 31P-magnetic resonance spectroscopy to study phosphocreatine (PCr) recovery in rat leg muscle after sciatic nerve stimulation at 1-4 Hz. We studied normal animals and animals with defective skeletal muscle mitochondrial function after experimental cardiac infarction. To analyze these data, we used three current theoretical approaches to the control of mitochondrial ATP synthesis, based on its hyperbolic relationship to cytosolic ADP concentration and on its linear relationships to PCr concentration and the free energy of ATP hydrolysis. The mitochondrial ADP concentration for one-half maximum rate of ATP synthesis appeared at least twice as high as the 30 microM expected from in vitro studies. According to all three approaches, the apparent maximum rate of ATP synthesis was independent of stimulation frequency and end-exercise pH and PCr and ADP concentrations and was reduced by approximately 50% after experimental cardiac infarction. Analysis of PCr recovery kinetics is a robust and practical way to study mitochondrial regulation and to quantify effective mitochondrial defects in vivo.

scholarly journals Comparison of in vivo postexercise phosphocreatine recovery and resting ATP synthesis flux for the assessment of skeletal muscle mitochondrial function

2010 ◽  
Vol 299 (5) ◽  
pp. C1136-C1143 ◽  
Author(s):  
N. M. A. van den Broek ◽  
J. Ciapaite ◽  
K. Nicolay ◽  
J. J. Prompers
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Atp Synthesis ◽  
Resonance Spectroscopy ◽  
Isolated Mitochondria ◽  
Significant Difference

31P magnetic resonance spectroscopy (MRS) has been used to assess skeletal muscle mitochondrial function in vivo by measuring 1) phosphocreatine (PCr) recovery after exercise or 2) resting ATP synthesis flux with saturation transfer (ST). In this study, we compared both parameters in a rat model of mitochondrial dysfunction with the aim of establishing the most appropriate method for the assessment of in vivo muscle mitochondrial function. Mitochondrial dysfunction was induced in adult Wistar rats by daily subcutaneous injections with the complex I inhibitor diphenyleneiodonium (DPI) for 2 wk. In vivo 31P MRS measurements were supplemented by in vitro measurements of oxygen consumption in isolated mitochondria. Two weeks of DPI treatment induced mitochondrial dysfunction, as evidenced by a 20% lower maximal ADP-stimulated oxygen consumption rate in isolated mitochondria from DPI-treated rats oxidizing pyruvate plus malate. This was paralleled by a 46% decrease in in vivo oxidative capacity, determined from postexercise PCr recovery. Interestingly, no significant difference in resting, ST-based ATP synthesis flux was observed between DPI-treated rats and controls. These results show that PCr recovery after exercise has a more direct relationship with skeletal muscle mitochondrial function than the ATP synthesis flux measured with 31P ST MRS in the resting state.

scholarly journals Early metabolic changes measured by 1H MRS in healthy and dystrophic muscle after injury

2012 ◽  
Vol 113 (5) ◽  
pp. 808-816 ◽  
Author(s):  
Su Xu ◽  
Stephen J. P. Pratt ◽  
Espen E. Spangenburg ◽  
Richard M. Lovering
Keyword(s):  
Skeletal Muscle ◽  
Muscle Injury ◽  
Tibialis Anterior Muscle ◽  
Metabolic Changes ◽  
Mdx Mice ◽  
Resonance Spectroscopy ◽  
Dystrophic Muscle ◽  
1H Mrs ◽  
Skeletal Muscle Injury

Skeletal muscle injury is often assessed by clinical findings (history, pain, tenderness, strength loss), by imaging, or by invasive techniques. The purpose of this work was to determine if in vivo proton magnetic resonance spectroscopy (1H MRS) could reveal metabolic changes in murine skeletal muscle after contraction-induced injury. We compared findings in the tibialis anterior muscle from both healthy wild-type (WT) muscles (C57BL/10 mice) and dystrophic ( mdx mice) muscles (an animal model for human Duchenne muscular dystrophy) before and after contraction-induced injury. A mild in vivo eccentric injury protocol was used due to the high susceptibility of mdx muscles to injury. As expected, mdx mice sustained a greater loss of force (81%) after injury compared with WT (42%). In the uninjured muscles, choline (Cho) levels were 47% lower in the mdx muscles compared with WT muscles. In mdx mice, taurine levels decreased 17%, and Cho levels increased 25% in injured muscles compared with uninjured mdx muscles. Intramyocellular lipids and total muscle lipid levels increased significantly after injury but only in WT. The increase in lipid was confirmed using a permeable lipophilic fluorescence dye. In summary, loss of torque after injury was associated with alterations in muscle metabolite levels that may contribute to the overall injury response in mdx mice. These results show that it is possible to obtain meaningful in vivo 1H MRS regarding skeletal muscle injury.

Differential effects of anesthetics on in vivo skeletal muscle contractile function in the mouse

1996 ◽  
Vol 80 (1) ◽  
pp. 332-340 ◽  
Author(s):  
C. P. Ingalls ◽  
G. L. Warren ◽  
D. A. Lowe ◽  
D. B. Boorstein ◽  
R. B. Armstrong
Keyword(s):  
Skeletal Muscle ◽  
Contractile Function ◽  
Average Power ◽  
Eccentric Contraction ◽  
Peak Torque ◽  
High Dose ◽  
Skeletal Muscle Function ◽  
Contractile Responses ◽  
Time Integral

The purpose of this study was to evaluate the effects of four anesthetic regimens on in vivo contractile function of mouse ankle dorsiflexor muscles. The torque-frequency and torque-velocity relationships were determined for the following anesthetics: fentanyl-droperidol and diazepam (F-d/d); ketamine and xylazine (K/x); pentobarbital sodium (Ps); and methoxyflurane (Mf). Mf, Ps, and F-d/d regimens resulted in comparable contractile responses at low doses, whereas K/x produced a relative depression in isometric contractile function as shown by a decrease in the torque-time integral at the 300-Hz stimulation frequency (-13.9%; P < 0.05). Moreover, K/x caused a shift to the left in the torque-frequency curve as indicated by increases in torque-time integrals at 25 and 50 Hz. Both Ps and F-d/d regimens exhibited dose-dependent effects during the isovelocity contractions. Ps significantly reduced work (-28.7%) and average power (-28.9%) at 800 degrees/s at the high dose. In contrast, F-d/d anesthesia resulted in increases in peak torque (16-20%) and work (15-18%) output at all eccentric contraction velocities at the high dose, whereas average power was increased only at -800 (17%) and -1,000 degrees/s (17%). In conclusion, commonly used anesthetic regimens can affect the contractile response in vivo; K/x and Ps yield smaller torque outputs, whereas Mf and F-d/d consistently produce larger contractile responses. Mf and F-d/d are recommended for use in studying skeletal muscle function in mice in vivo.

Responses of skeletal muscle lipid metabolism in rat gastrocnemius to hypothyroidism and iodothyronine administration: a putative role for FAT/CD36

2012 ◽  
Vol 303 (10) ◽  
pp. E1222-E1233 ◽  
Author(s):  
Assunta Lombardi ◽  
Rita De Matteis ◽  
Maria Moreno ◽  
Laura Napolitano ◽  
Rosa Anna Busiello ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Protein Level ◽  
Oxidation Rate ◽  
Mitochondrial Protein ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Muscle Lipid ◽  
Mitochondrial Fatty Acid ◽  
Skeletal Muscle Lipid

Iodothyronines such as triiodothyronine (T3) and 3,5-diiodothyronine (T2) influence energy expenditure and lipid metabolism. Skeletal muscle contributes significantly to energy homeostasis, and the above iodothyronines are known to act on this tissue. However, little is known about the cellular/molecular events underlying the effects of T3 and T2 on skeletal muscle lipid handling. Since FAT/CD36 is involved in the utilization of free fatty acids by skeletal muscle, specifically in their import into that tissue and presumably their oxidation at the mitochondrial level, we hypothesized that related changes in lipid handling and in FAT/CD36 expression and subcellular redistribution would occur due to hypothyroidism and to T3 or T2 administration to hypothyroid rats. In gastrocnemius muscles isolated from hypothyroid rats, FAT/CD36 was upregulated (mRNA levels and total tissue, sarcolemmal, and mitochondrial protein levels). Administration of either T3 or T2 to hypothyroid rats resulted in 1) little or no change in FAT/CD36 mRNA level, 2) a decreased total FAT/CD36 protein level, and 3) further increases in FAT/CD36 protein level in sarcolemma and mitochondria. Thus, the main effect of each iodothyronine seemed to be exerted at the level of FAT/CD36 cellular distribution. The effect of further increases in FAT/CD36 protein level in sarcolemma and mitochondria was already evident at 1 h after iodothyronine administration. Each iodothyronine increased the mitochondrial fatty acid oxidation rate. However, the mechanisms underlying their rapid effects seem to differ; T2 and T3 each induce FAT/CD36 translocation to mitochondria, but only T2 induces increases in carnitine palmitoyl transferase system activity and in the mitochondrial substrate oxidation rate.

scholarly journals Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content

2000 ◽  
Vol 89 (1) ◽  
pp. 104-110 ◽  
Author(s):  
Bret H. Goodpaster ◽  
David E. Kelley ◽  
F. Leland Thaete ◽  
Jing He ◽  
Robert Ross
Keyword(s):  
Skeletal Muscle ◽  
Lipid Content ◽  
Ct Scans ◽  
Lipid Concentration ◽  
Muscle Lipid ◽  
Muscle Attenuation ◽  
Good Concordance ◽  
Type 2 Diabetic

The purpose of this investigation was to validate that in vivo measurement of skeletal muscle attenuation (MA) with computed tomography (CT) is associated with muscle lipid content. Single-slice CT scans performed on phantoms of varying lipid concentrations revealed good concordance between attenuation and lipid concentration ( r 2 = 0.995); increasing the phantom's lipid concentration by 1 g/100 ml decreased its attenuation by ∼1 Hounsfield unit (HU). The test-retest coefficient of variation for two CT scans performed in six volunteers was 0.51% for the midthigh and 0.85% for the midcalf, indicating that the methodological variability is low. Lean subjects had significantly higher ( P < 0.01) MA values (49.2 ± 2.8 HU) than did obese nondiabetic (39.3 ± 7.5 HU) and obese Type 2 diabetic (33.9 ± 4.1 HU) subjects, whereas obese Type 2 diabetic subjects had lower MA values that were not different from obese nondiabetic subjects. There was also good concordance between MA in midthigh and midcalf ( r = 0.60, P < 0.01), psoas ( r = 0.65, P < 0.01), and erector spinae ( r = 0.77, P < 0.01) in subsets of volunteers. In 45 men and women who ranged from lean to obese (body mass index = 18.5 to 35.9 kg/m2), including 10 patients with Type 2 diabetes mellitus, reduced MA was associated with increased muscle fiber lipid content determined with histological oil red O staining ( P = −0.43, P < 0.01). In a subset of these volunteers ( n = 19), triglyceride content in percutaneous biopsy specimens from vastus lateralis was also associated with MA ( r = −0.58, P = 0.019). We conclude that the attenuation of skeletal muscle in vivo determined by CT is related to its lipid content and that this noninvasive method may provide additional information regarding the association between muscle composition and muscle function.

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