Proliferation of Human Primary Myoblasts Is Associated with Altered Energy Metabolism in Dependence on Ageing<i>In Vivo</i>and<i>In Vitro</i>

Pääsuke, Reedik; Eimre, Margus; Piirsoo, Andres; Peet, Nadezhda; Laada, Liidia; Kadaja, Lumme; Roosimaa, Mart; Märtson, Aare; Seppet, Enn; Paju, Kalju

doi:10.1155/2016/8296150

Cited by 22 publications

(27 citation statements)

References 55 publications

(42 reference statements)

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“…This phenomenon is described as the Warburg effect or aerobic glycolysis and it has been proposed to facilitate the uptake and incorporation of nutrients needed to produce a new cell50. In fact, we also observed a disturbance in the cell cycle population with an increased proliferative state of MDC1A and Surf1-LS myoblasts, which confirms recent findings which associated proliferation of myoblasts in vitro with downregulation of OXPHOS and energy storage in ageing52. In addition, following differentiation we observed increased apoptosis in myotubes, confirming that bioenergetic impairment may lead to a disturbance in the cell cycle and late apoptosis in MDC1A and Surf1-LS.…”

Section: Discussionsupporting

confidence: 90%

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Fontes-Oliveira

Steinz

Schneiderat³

et al. 2017

Sci Rep

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Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients.

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Section: Discussionsupporting

confidence: 90%

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Fontes-Oliveira

Steinz

Schneiderat³

et al. 2017

Sci Rep

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“…A previous study demonstrated that proliferation of myoblasts is highly dependent on OXPHOS by the mitochondrial respiratory chain (Pääsuke et al, ). We, therefore, analyzed oxygen consumption by ESR.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

et al. 2019

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Ubiquitin‐specific protease 2 (USP2) is considered to participate in the differentiation of myoblasts to myotubes, however, its functions in myoblasts under growth conditions remain elusive. In this study, we analyzed the physiological roles of USP2 in myoblasts using Usp2 knockout (KO) C2C12 cells as well as a USP2 specific inhibitor. In addition to the disruption of differentiation, clustered regularly interspaced short palindromic repeats/Cas9‐generated Usp2 KO cells exhibited inhibition of proliferation compared to parental C2C12 cells. Usp2 KO cells reduced the accumulation of intracellular adenosine triphosphate (ATP) content and oxygen consumption. Moreover, Usp2 KO cells had fragmented mitochondria, suggesting that mitochondrial respiration was inactive. The deficiency of Usp2 did not affect the enzymatic activities of respiratory chain complexes I, III, IV, and V. However, mitochondrial membrane permeability—evaluated using calcein AM‐cobalt staining—was increased in Usp2 KO cells. The membrane potential of Usp2 KO cells was clearly decreased. Usp2 KO cells accumulated reactive oxygen species (ROS) in the mitochondria. The USP2‐selective inhibitor ML364 also increased the levels of mitochondrial ROS, and modulated the membrane potential and morphology of the mitochondria. These effects were followed by a decrement in the intracellular content of ATP. Based on these findings, we speculate that USP2 may be involved in maintaining the integrity of the mitochondrial membrane. This process ensures the supply of ATP in myoblasts, presumably leading to proliferation and differentiation.

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“…Ageing processes are characterized by decline in immune responses (Xu et al, ), alterations of gut microbiota (Biagi et al, ), and changes in the nutrient sensing pathway (Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, ). In particular, ageing in vivo decreases enzymatic activities participating in energy metabolism and the rate of oxidative phosphorylation resulting in an altered metabolic profile, which is shown as a metabolic shift from mitochondrial respiration to glycolysis in myoblasts (Paasuke et al, ). Based on gas chromatography‐mass spectrometry metabolomics, six amino acids (proline, methionine, 4‐hydroxyproline, pipecolic acid, glutamic acid, and α‐aminoadipic acid), and five organic acids (2‐hydroxybutyric acid, 2‐hydroxyglutaric acid, cis‐aconitic acid, citric acid, and isocitric acid) were identified as potential biomarkers for metabolic differences between young (8 weeks) and old mice (72 weeks) (Seo et al, ), suggesting the involvement of amino acid and energy metabolism in the ageing processes.…”

Section: Discussionmentioning

confidence: 99%

“…Ageing processes are characterized by decline in immune responses , alterations of gut microbiota (Biagi et al, 2010), and changes in the nutrient sensing pathway (Lopez-Otin, Blasco, Partridge, Serrano, & Kroemer, 2013). In particular, ageing in vivo decreases enzymatic activities participating in energy metabolism and the rate of oxidative phosphorylation resulting in an altered metabolic profile, which is shown as a metabolic shift from mitochondrial respiration to glycolysis in myoblasts (Paasuke et al, 2016). Based on FIG URE 2 PCA score plots based on 1 H NMR spectra data of urine samples from normal aged mice (green star, n 5 7) and L2treated aged mice (yellow triangle, n 5 7)…”

Section: Discussionmentioning

confidence: 99%

¹H NMR-based metabolic investigation of the effect ofLentinula edodes-derived polysaccharides on aged mice

Yang

Zheng-xiang

et al. 2017

Journal of Food Biochemistry

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Few comprehensive metabolic profiles of Lentinula edodes‐derived polysaccharides on mammalians have been reported to date. In previous studies, a novel heteropolysaccharide, named L2, obtained from L. edodes had shown anti‐ageing effects in mice. In this study, a 1H NMR‐based metabolomics approach was used to investigate the urinary metabolome changes in aged mice gavaged with L2 for better understanding of anti‐ageing mechanism. Six metabolites in urine were identified as potential markers for L2 treatment. An increase in α‐oxoglutarate (α‐OG) and a decrease in β‐hydroxybutyrate, glutamate, glucose, choline, and lactate were observed. Enrichment pathway analysis indicated that 11 metabolic pathways were disrupted after L2 treatment. These altered metabolic pathways are mainly associated with energy metabolism, amino acid metabolism, and glycolysis. The results suggest that L2 could exert anti‐ageing effects partly by regulating these pathways. Moreover, these findings may help better understand the mechanisms of the bioactivities of L. edodes‐derived polysaccharides. Practical applications In this study, a 1H NMR‐based metabolomics approach was used to investigate the urinary metabolome changes in aged mice gavaged with a novel heteropolysaccharide L2 from Lentinula edodes. The findings may help better understand the mechanisms of bioactivities of L. edodes‐derived polysaccharides, and used for further development of L2 in food and medicine.

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Proliferation of Human Primary Myoblasts Is Associated with Altered Energy Metabolism in Dependence on AgeingIn VivoandIn Vitro

Cited by 22 publications

References 55 publications

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

¹H NMR-based metabolic investigation of the effect ofLentinula edodes-derived polysaccharides on aged mice

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Proliferation of Human Primary Myoblasts Is Associated with Altered Energy Metabolism in Dependence on AgeingIn VivoandIn Vitro

Cited by 22 publications

References 55 publications

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

1H NMR-based metabolic investigation of the effect ofLentinula edodes-derived polysaccharides on aged mice

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¹H NMR-based metabolic investigation of the effect ofLentinula edodes-derived polysaccharides on aged mice