Carnitine supplementation to obese Zucker rats prevents obesity-induced type I to type II muscle fiber transition and favors an oxidative phenotype of skeletal muscle

Couturier, Aline; Ringseis, Robert; Mooren, Frank-Christoph; Krüger, Karsten; Most, Erika; Eder, Klaus

doi:10.1186/1743-7075-10-48

Cited by 35 publications

(35 citation statements)

References 41 publications

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“…It is well known that the carnitine status in obese Zucker rats and other models of genetic and diet-induced obesity is markedly impaired and as a consequence several metabolic disturbances are induced [31–33]. In contrast, supplementation with carnitine improves carnitine status, which was also demonstrated in the present study, and reverses to a great part these metabolic disturbances, like elevated blood levels of triacylglycerides and non-esterified fatty acids, glucose intolerance and insulin resistance [30–32, 34]. The key finding of the present study is that carnitine supplementation resulted in a profound change in the miRNA expression profile in skeletal muscle of obese Zucker rats suggesting a novel regulatory mechanism by which dietary carnitine alters gene expression and mediates at least some of its biological effects.…”

Section: Discussionsupporting

confidence: 80%

Supplemental carnitine affects the microRNA expression profile in skeletal muscle of obese Zucker rats

2014

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BackgroundIn the past, numerous studies revealed that supplementation with carnitine has multiple effects on performance characteristics and gene expression in livestock and model animals. The molecular mechanisms underlying these observations are still largely unknown. Increasing evidence suggests that microRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing several physiological and pathological processes. Based on these findings, the aim of the present study was to investigate the influence of carnitine supplementation on the miRNA expression profile in skeletal muscle of obese Zucker rats using miRNA microarray analysis.ResultsObese Zucker rats supplemented with carnitine had higher concentrations of total carnitine in plasma and muscle than obese control rats (P < 0.05). miRNA expression profiling in skeletal muscle revealed a subset of 152 miRNAs out of the total number of miRNAs analysed (259) were identified to be differentially regulated (adjusted P-value < 0.05) by carnitine supplementation. Compared to the obese control group, 111 miRNAs were up-regulated and 41 down-regulated by carnitine supplementation (adjusted P-value < 0.05). 14 of these miRNAs showed a log2 ratio ≥ 0.5 and 7 miRNAs showed a log2 ratio ≤ −0.5 (adjusted P-value < 0.05). After confirmation by qRT-PCR, 11 miRNAs were found to be up-regulated and 6 miRNAs were down-regulated by carnitine supplementation (P < 0.05). Furthermore, a total of 1,446 target genes within the validated miRNAs were revealed using combined three bioinformatic algorithms. Analysis of Gene Ontology (GO) categories and KEGG pathways of the predicted targets revealed that carnitine supplementation regulates miRNAs that target a large set of genes involved in protein-localization and -transport, regulation of transcription and RNA metabolic processes, as well as genes involved in several signal transduction pathways, like ubiquitin-mediated proteolysis and longterm depression, are targeted by the miRNAs regulated by carnitine supplementation.ConclusionThe present study shows for the first time that supplementation of carnitine affects a large set of miRNAs in skeletal muscle of obese Zucker rats suggesting a novel mechanism through which carnitine exerts its multiple effects on gene expression, which were observed during the past.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-512) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 80%

Supplemental carnitine affects the microRNA expression profile in skeletal muscle of obese Zucker rats

2014

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“…In adult rodents, insulin resistance in skeletal muscle is associated with an increased prevalence of type IIb muscle fibers . In the current study, MHC type I fiber protein and mRNA levels were increased in the gastrocnemius muscle of OLETF‐C rats compared with LETO‐C rats ( P < 0.05; Figure C).…”

Section: Discussionsupporting

confidence: 52%

Long‐term insulin treatment leads to a change in myosin heavy chain fiber distribution in OLETF rat skeletal muscle

Hong

Choi

Kwon

et al. 2018

J of Cellular Biochemistry

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The objective of this study was to investigate molecular and physiological changes in response to long-term insulin glargine treatment in the skeletal muscle of OLETF rats. Male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats aged 24 weeks were randomly allocated to either treatment with insulin for 24 weeks or no treatment, resulting in three groups. Insulin glargine treatment in OLETF rats (OLETF-G) for 24 weeks resulted in changes in blood glucose levels in intraperitoneal glucose tolerance tests compared with age-matched, untreated OLETF rats (OLETF-C), and the area under the curve was significantly decreased for OLETF-G rats compared with OLETF-C rats (P < 0.05). The protein levels of MHC isoforms were altered in gastrocnemius muscle of OLETF rats, and the proportions of myosin heavy chain type I and II fibers were lower and higher, respectively, in OLETF-G compared with OLETF-C rats. Activation of myokines (IL-6, IL-15, FNDC5, and myostatin) in gastrocnemius muscle was significantly inhibited in OLETF-G compared with OLETF-C rats ( P < 0.05). MyoD and myogenin levels were decreased, while IGF-I and GLUT4 levels were increased, in the skeletal muscle of OLETF-G rats ( P < 0.05). Insulin glargine treatment significantly increased the phosphorylation levels of AMPK, SIRT1, and PGC-1α. Together, our results suggested that changes in the distribution of fiber types by insulin glargine could result in downregulation of myokines and muscle regulatory proteins. The effects were likely associated with activation of the AMPK/SIRT1/PGC-1α signaling pathway. Changes in these proteins may at least partly explain the effect of insulin in skeletal muscle of diabetes mellitus.

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“…D, Comparison between mean values of the area percentage of MHC type IIa among the studied groups. 46 Crunkhorn et al 47 demonstrated that reduced expression of PGC-1α in skeletal muscle of HFD-induced obesity is attributed to muscle insulin resistance and excess nutrients especially fatty acids, also, insulin enhanced the expression of PGC-1α in human skeletal muscles and this expression was positively related to glucose uptake and oxidation. HFD, high-fat diet; MHC, myosin heavy chain muscle.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of metformin on muscle atrophy induced by obesity in rats

Hasan

Shalaby

El‐Gendy

et al. 2018

J of Cellular Biochemistry

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Aim A growing interest to understand the signaling pathways mediating obesity‐induced muscle atrophy is given. Metformin (Met) was reported to possess positive effects on preventing muscle damage and promoting muscle mass maintenance. The aim of the present study to investigate pathways involved in Met effect on obesity induced muscle atrophy. Methods Thirty adult male albino rats were assigned into two groups: normal chew diet fed group as control group (C; n = 10) and high‐fat‐diet (HFD) fed group ( n = 20). After 16 weeks, the HFD‐fed animals were subdivided into two groups; HFD group ( n = 10) and HFD fed treated with oral Met (320 mg/day) treatment (Met, n = 10) for 4 weeks. At the end of the experiment; final body weight, visceral fat weight, fasting blood glucose, insulin, lactate, total cholesterol, triglycerides were measured and calculated homeostatic model assessment insulin resistant (HOMA‐IR) for all groups. Soleus muscle weight, histopathlogical examination and expression of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), forkhead box O3 (FoxO3), atrogin‐1/MAFbx, and muscle RING finger 1 (MuRF‐1) were performed. Results HFD‐fed animals showed significant increase in final body weight, visceral fat mass, fasting blood glucose, insulin, calculated HOMA‐IR, lactate, total cholesterol and triglycerides with significant decrease in soleus muscle weight, PGC‐1α and significant increase in FoxO3, atrogin‐1/MAFbx, and MuRF‐1 expression. Also, there was significant decrease in fiber diameter, myosin heavy chain (MHC) I content while collagen content and myosin heavy chain IIa were increased compared with control group. Met‐treated group showed a significant decrease in the measured parameters compared with the HFD group. It also restored the gene expression, morphometric measures and MHC composition toward normal. Conclusion The current study is the first to provide evidence that Met could ameliorate muscle atrophy in high‐fat diet induced obesity and this effect may be in part due to regulation of PGC‐1α‐FoxO3 pathway.

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Carnitine supplementation to obese Zucker rats prevents obesity-induced type I to type II muscle fiber transition and favors an oxidative phenotype of skeletal muscle

Cited by 35 publications

References 41 publications

Supplemental carnitine affects the microRNA expression profile in skeletal muscle of obese Zucker rats

Supplemental carnitine affects the microRNA expression profile in skeletal muscle of obese Zucker rats

Long‐term insulin treatment leads to a change in myosin heavy chain fiber distribution in OLETF rat skeletal muscle

Beneficial effects of metformin on muscle atrophy induced by obesity in rats

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