Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice

Nunes, Patrícia M.; Weijer, Tineke van de; Veltien, Andor; Arnts, H.F.G.; Hesselink, Matthijs K. C.; Glatz, Jan F. C.; Schrauwen, Patrick; Tack, Cees J.; Heerschap, Arend

doi:10.1152/ajpendo.00597.2011

Cited by 16 publications

(21 citation statements)

References 55 publications

(74 reference statements)

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“…Unexpectedly, changes in ATGL-mediated TAG hydrolysis in skeletal muscle in vivo do not significantly impact these parameters. These results are consistent with reports demonstrating IMTG accumulation but unaltered in vivo mitochondrial function in skeletal muscle of GAKO (42) and muscle-specific CGI-58 knockout mice (43). Thus, in striking contrast to cardiac muscle (21), in vivo modulation of TAG hydrolysis in skeletal muscle does not influence PPAR target genes or mitochondrial phenotypes.…”

Section: Discussionsupporting

confidence: 93%

Skeletal Muscle Triacylglycerol Hydrolysis Does Not Influence Metabolic Complications of Obesity

et al. 2013

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Intramyocellular triacylglycerol (IMTG) accumulation is highly associated with insulin resistance and metabolic complications of obesity (lipotoxicity), whereas comparable IMTG accumulation in endurance-trained athletes is associated with insulin sensitivity (the athlete’s paradox). Despite these findings, it remains unclear whether changes in IMTG accumulation and metabolism per se influence muscle-specific and systemic metabolic homeostasis and insulin responsiveness. By mediating the rate-limiting step in triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL) has been proposed to influence the storage/production of deleterious as well as essential lipid metabolites. However, the physiological relevance of ATGL-mediated triacylglycerol hydrolysis in skeletal muscle remains unknown. To determine the contribution of IMTG hydrolysis to tissue-specific and systemic metabolic phenotypes in the context of obesity, we generated mice with targeted deletion or transgenic overexpression of ATGL exclusively in skeletal muscle. Despite dramatic changes in IMTG content on both chow and high-fat diets, modulation of ATGL-mediated IMTG hydrolysis did not significantly influence systemic energy, lipid, or glucose homeostasis, nor did it influence insulin responsiveness or mitochondrial function. These data argue against a role for altered IMTG accumulation and lipolysis in muscle insulin resistance and metabolic complications of obesity.

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Section: Discussionsupporting

confidence: 93%

Skeletal Muscle Triacylglycerol Hydrolysis Does Not Influence Metabolic Complications of Obesity

et al. 2013

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“…Interestingly, our findings are similar to those recently reported in adipose triglyceride lipase knockout (ATGL-KO) mice in which the force production was lower as compared to controls while a similar PCr depletion was observed for the two groups. The authors also concluded that ATGL-KO mice had a higher energy cost per contraction (or a lower contractile efficiency) as compared to controls [41].…”

Section: Discussionmentioning

confidence: 98%

“…Over the last decade, analysis of PCr recovery kinetics has been extensively used in order to investigate in vivo skeletal muscle mitochondrial oxidative capacity [41], [42]. Previous animal studies reported PCr recovery times typically ranging from ∼50 sec to ∼160 sec according to the end-of-exercise pH values [31], [41], [43]. From a methodological point of view, it should be pointed out that PCr recovery is usually fitted with a monoexponential function so that the temporal resolution of the raw dataset is of utmost importance for an accurate measurement of the corresponding variables.…”

Section: Discussionmentioning

confidence: 99%

Combined MRI and 31P-MRS Investigations of the ACTA1(H40Y) Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy Metabolism

et al. 2013

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Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene (ACTA1) account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and 31Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1–150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (−40%) and specific (−25%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.

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“…Intramyocellular lipid (IMCL) levels were assessed by single‐voxel 1 H MRS at 7 T from the tibialis anterior muscle as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose‐ compared to glucose‐fed mice

et al. 2014

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Fructose consumption has been associated with the surge in obesity and dyslipidemia. This may be mediated by the fructose effects on hepatic lipids and ATP levels. Fructose metabolism provides carbons for de novo lipogenesis (DNL) and stimulates enterocyte secretion of apoB48. Thus, fructose-induced hepatic triglyceride (HTG) accumulation can be attributed to both DNL stimulation and dietary lipid absorption. The aim of this study was to assess the effects of fructose diet on HTG and ATP content and the contributions of dietary lipids and DNL to HTG. Measurements were performed in vivo in mice by magnetic resonance imaging (MRI) and novel magnetic resonance spectroscopy (MRS) approaches. Abdominal adipose tissue volume and intramyocellular lipid levels were comparable between 8-wk fructose- and glucose-fed mice. HTG levels were ∼1.5-fold higher in fructose-fed than in glucose-fed mice (P<0.05). Metabolic flux analysis by (13)C and (2)H MRS showed that this was not due to dietary lipid absorption, but due to DNL stimulation. The contribution of oral lipids to HTG was, after 5 h, 1.60 ± 0.23% for fructose and 2.16 ± 0.35% for glucose diets (P=0.26), whereas that of DNL was higher in fructose than in glucose diets (2.55±0.51 vs.1.13±0.24%, P=0.01). Hepatic energy status, assessed by (31)P MRS, was similar for fructose- and glucose-fed mice. Fructose-induced HTG accumulation is better explained by DNL and not by dietary lipid uptake, while not compromising ATP homeostasis.

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Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice

Cited by 16 publications

References 55 publications

Skeletal Muscle Triacylglycerol Hydrolysis Does Not Influence Metabolic Complications of Obesity

Skeletal Muscle Triacylglycerol Hydrolysis Does Not Influence Metabolic Complications of Obesity

Combined MRI and 31P-MRS Investigations of the ACTA1(H40Y) Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy Metabolism

Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose‐ compared to glucose‐fed mice

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