Skeletal Muscle Nucleo-Mitochondrial Crosstalk in Obesity and Type 2 Diabetes

Devarshi, Prasad P.; McNabney, Sean M.; Henagan, Tara M.

doi:10.3390/ijms18040831

Cited by 34 publications

(27 citation statements)

References 165 publications

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“…(13,22) In the setting of diabetes, our data showed significant differences in several key intermediates of fatty acid metabolism including pyruvate and malate, consistent with other studies. (23) Interestingly, we found branched chained ACs to be associated with diabetes but not the corresponding AAs as has been described elsewhere. The reasons for this are unclear but could suggest increased utilization in the setting of HF that partially offsets the diabetes effect.…”

Section: Discussionsupporting

confidence: 81%

Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients

Lanfear¹,

Gibbs²,

Li³

et al. 2017

JACC: Heart Failure

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Background Profiling of plasma metabolites to predict the course of heart failure (HF) appears promising but validation and incremental value are less established. Methods Patients meeting Framingham HF criteria with history of reduced ejection fraction were (n=1032) were randomly divided into derivation and validation cohorts (n=516 each). Amino acids, organic acids, and acylcarnitines were quantified using mass spectrometry in fasting plasma samples. We derived a prognostic metabolite profile (PMP) in the derivation cohort using Lasso-penalized Cox regression. Validity was assessed by 10-fold cross-validation in the derivation cohort, and by standard testing in the validation cohort. The PMP was analyzed as both a continuous variable (PMPscore) and dichotomized at the median (PMPcat), in univariate and multivariate models adjusted for clinical risk score and NTproBNP. Results Overall 48% of patients were African American, 35% were female, and average age was 69 years. After median follow-up of 34 months, there were 256 deaths (127 and 129 in derivation and validation cohorts, respectively). Optimized modeling defined the 13 metabolite PMP, which cross-validated as both PMPscore (hazard ratio [HR] 3.27, p<2×10−16) and PMPcat (HR=3.04, p=2.93×10−8). The validation cohort showed similar results; PMPscore HR=3.9 (p<2×10−16) and PMPcat HR=3.99 (p=3.47×10−9). In adjusted models PMP remained associated with mortality in the cross-validated derivation cohort (PMPscore HR=1.63, p=0.0029; PMPcat HR=1.47, p=0.081) and validation cohort (PMPscore HR=1.54, p=0.037; PMPcat HR=1.69, p=0.043). Conclusion Plasma metabolite profile varies across HF subgroups and is associated with survival incremental to conventional predictors. Additional investigation is warranted to define mechanisms and clinical applications.

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Section: Discussionsupporting

confidence: 81%

Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients

Lanfear¹,

Gibbs²,

Li³

et al. 2017

JACC: Heart Failure

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“…The present data also suggest that SP enhances muscle energy expenditure by upregulating transcription factors involved in mitochondrial biogenesis: PGC-1α NRF1 and UCP3, which themselves upregulate GLUT4 expression [61]. Recent research reported that muscle mitochondrial-related genes, including NRF1, PGC1α, and UCP3, regulate insulin resistance during obesity [62,63]. In particular, PGC1α is a well-known transcription factor correlated with sarcopenia and metabolic disease during aging [64,65].…”

Section: Discussionsupporting

confidence: 65%

Effect of Dietary Silk Peptide on Obesity, Hyperglycemia, and Skeletal Muscle Regeneration in High-Fat Diet-Fed Mice

Lee

Jin

Chei

et al. 2020

Cells

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Obesity is associated with excess body fat accumulation that can cause hyperglycemia and reduce skeletal muscle function and strength, which characterize the development of sarcopenic obesity. In this study, we aimed to determine the mechanism whereby acid-hydrolyzed silk peptide (SP) prevents high-fat diet (HFD)-induced obesity and whether it regulates glucose uptake and muscle differentiation using in vivo and in vitro approaches. Our findings demonstrate that SP inhibits body mass gain and the expression of adipogenic transcription factors in visceral adipose tissue (VAT). SP also had an anti-diabetic effect in VAT and skeletal muscle because it upregulated glucose transporter type 4 (GLUT4) and uncoupling protein 3 (UCP3) expression. Furthermore, SP reduced ubiquitin proteasome and promoted myoblast determination protein 1 (MyoD)/myogenic factor 4 (myogenin) expression, implying that it may have potential for the treatment of obesity-induced hyperglycemia and obesity-associated sarcopenia.

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“…A high NADH/NAD + ratio leads to inactivation of mitochondrial and nuclear SIRT deacetylases, reducing mitochondrial biogenesis and activity ( 42 ). Indeed, prolonged high-fat feeding of rodents or continuous fatty acid exposure of myotubes leads to a reduction in nuclear-encoded mitochondrial genes ( 43 ). A reduction in β -oxidation can cause accumulation of long-chain fatty acyl-CoA, diacylglycerol, triacylglycerol, and ceramide, which may increase serine phosphorylation of the insulin receptor and reduce activation of Akt/PKB, leading to impaired insulin signaling ( 44 ).…”

Section: Physiological Relevance Of Metabolic Flexibilitymentioning

confidence: 99%

Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

et al. 2018

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The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, dependent on availability and requirement, is known as metabolic flexibility. In this review, we discuss the breadth and depth of metabolic flexibility and its impact on health and disease. Metabolic flexibility is essential to maintain energy homeostasis in times of either caloric excess or caloric restriction, and in times of either low or high energy demand, such as during exercise. The liver, adipose tissue, and muscle govern systemic metabolic flexibility and manage nutrient sensing, uptake, transport, storage, and expenditure by communication via endocrine cues. At a molecular level, metabolic flexibility relies on the configuration of metabolic pathways, which are regulated by key metabolic enzymes and transcription factors, many of which interact closely with the mitochondria. Disrupted metabolic flexibility, or metabolic inflexibility, however, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer. Multiple factors such as dietary composition and feeding frequency, exercise training, and use of pharmacological compounds, influence metabolic flexibility and will be discussed here. Last, we outline important advances in metabolic flexibility research and discuss medical horizons and translational aspects.

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Skeletal Muscle Nucleo-Mitochondrial Crosstalk in Obesity and Type 2 Diabetes

Cited by 34 publications

References 165 publications

Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients

Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients

Effect of Dietary Silk Peptide on Obesity, Hyperglycemia, and Skeletal Muscle Regeneration in High-Fat Diet-Fed Mice

Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

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