Effect of metformin on myotube BCAA catabolism

Rivera, Madison E.; Lyon, Emily S.; Vaughan, Roger A.

doi:10.1002/jcb.29327

Cited by 22 publications

(30 citation statements)

References 36 publications

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“…Current evidence indicates that Metformin, a widely prescribed antidiabetic drug, lowers BCAAs ( Rivera et al, 2020 ) and keto acids, such as ketoisocaproic acid (KIC) ( Sonnet et al, 2016 ). We therefore hypothesized that Metformin could be beneficial in treating MSUD by offering protection against the detrimental effects provoked by high BCAA levels observed as a result of dDBT deficiency.…”

Section: Resultsmentioning

confidence: 99%

Loss of the Drosophila branched-chain α-keto acid dehydrogenase complex (BCKDH) results in neuronal dysfunction

Tsai

et al. 2020

Disease Models &Amp; Mechanisms

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Maple syrup urine disease (MSUD) is an inherited error in the metabolism of branched-chain amino acids (BCAAs) caused by a severe deficiency of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which ultimately leads to neurological disorders. The limited therapies, including protein-restricted diets and liver transplants, are not as effective as they could be for the treatment of MSUD due to the current lack of molecular insights into the disease pathogenesis. To address this issue, we developed a Drosophila model of MSUD by knocking out the dDBT gene, an ortholog of the human gene encoding the dihydrolipoamide branched chain transacylase (DBT) subunit of BCKDH. The homozygous dDBT mutant larvae recapitulate an array of MSUD phenotypes, including aberrant BCAA accumulation, developmental defects, poor mobile behavior and disrupted L-glutamate homeostasis. Moreover, the dDBT mutation causes neuronal apoptosis during the developmental progression of larval brains. The genetic and functional evidence generated by in vivo depletion of dDBT expression in the eye indicates severe impairment of retinal rhabdomeres. Further, the dDBT mutant shows elevated oxidative stress and higher lipid peroxidation accumulation in the larval brain. Therefore, we conclude from in vivo evidence that the loss of dDBT results in oxidative brain damage that may lead to neuronal cell death and contribute to aspects of MSUD pathology. Importantly, when the dDBT mutants were administrated with Metformin, the aberrances in BCAA levels and motor behavior were ameliorated. This intriguing outcome strongly merits the use of the dDBT mutant as a platform for developing MSUD therapies.This article has an associated First Person interview with the joint first authors of the paper.

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Section: Resultsmentioning

confidence: 99%

Loss of the Drosophila branched-chain α-keto acid dehydrogenase complex (BCKDH) results in neuronal dysfunction

Tsai

et al. 2020

Disease Models &Amp; Mechanisms

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“…Metformin is an inexpensive, well-tolerated, and widely prescribed drug which led to re-purposing appeal for metformin use in other diseases beyond T2D [ 88 ]. Mechanistically, metformin action is complex and may be dose and tissue dependent, but has been observed to signal through AMPKα and PGC-1α in many cell types, including hepatocytes and skeletal muscle [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. The pleiotropic effects of metformin make it difficult to delineate an exact mechanism but contribute to excitement as a therapy for targeting multiple facets dysregulated with disease and aging [ 88 ].…”

Section: Nutritional Therapies Combined With Metforminmentioning

confidence: 99%

Section: Nutritional Therapies Combined With Metforminmentioning

confidence: 99%

“…Metformin is known to increase PGC-1α in skeletal muscle tissue and cells [ 91 , 94 ], but AMPKα dependance is unknown. In C2C12 myotubes, metformin is able to increase PGC-1α mRNA [ 94 ]. In mouse muscle, metformin increased AMPKα and PGC-1α expression in slow- and fast-twitch fibers, indicating that metformin can increase PGC-1α regardless of muscle fiber type [ 91 ].…”

Section: Nutritional Therapies Combined With Metforminmentioning

confidence: 99%

“…For instance, in primary mouse hepatocytes treated with dexamethasone, 8 h of suprapharmacological metformin doses (1 and 2 mM) given with cyclic AMP decreased PGC-1α mRNA expression [ 105 ], whereas human primary hepatocytes exposed to 1 mM metformin for 48 h increased PGC-1α mRNA [ 106 ]. Further, in C2C12 myotubes, exposure of a single suprapharmacological metformin dose (2 mM) for 4, 8, 12 or 24 h increased PGC-1α mRNA expression, where a pharmacological dose (30 μM) did not during the same time course [ 94 ]. Metformin dosing also appears to alter mitochondrial function.…”

Section: Nutritional Therapies Combined With Metforminmentioning

confidence: 99%

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PGC-1α-Targeted Therapeutic Approaches to Enhance Muscle Recovery in Aging

Petrocelli

Drummond

2020

IJERPH

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Impaired muscle recovery (size and strength) following a disuse period commonly occurs in older adults. Many of these individuals are not able to adequately exercise due to pain and logistic barriers. Thus, nutritional and pharmacological therapeutics, that are translatable, are needed to promote muscle recovery following disuse in older individuals. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be a suitable therapeutic target due to pleiotropic regulation of skeletal muscle. This review focuses on nutritional and pharmacological interventions that target PGC-1α and related Sirtuin 1 (SIRT1) and 5′ AMP-activated protein kinase (AMPKα) signaling in muscle and thus may be rapidly translated to prevent muscle disuse atrophy and promote recovery. In this review, we present several therapeutics that target PGC-1α in skeletal muscle such as leucine, β-hydroxy-β-methylbuyrate (HMB), arginine, resveratrol, metformin and combination therapies that may have future application to conditions of disuse and recovery in humans.

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Effects of Metformin and its Metabolite Guanylurea on Fathead Minnow (Pimephales promelas) Reproduction

Blackwell

Ankley

Cavallin

et al. 2022

Enviro Toxic and Chemistry

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Metformin, along with its biotransformation product guanylurea, is commonly observed in municipal wastewaters and subsequent surface waters. Previous studies in fish have identified metformin as a potential endocrine-active compound, but there are inconsistencies with regard to its effects. To further investigate the potential reproductive toxicity of metformin and guanylurea to fish, a series of experiments was performed with adult fathead minnows (Pimephales promelas). First, explants of fathead minnow ovary tissue were exposed to 0.001-100 µM metformin or guanylurea to investigate whether the compounds could directly perturb steroidogenesis. Second, spawning pairs of fathead minnows were exposed to metformin (0.41, 4.1, and 41 µg/L) or guanylurea (1.0, 10, and 100 µg/L) for 23 days to assess impacts on reproduction. Lastly, male fathead minnows were exposed to 41 µg/L metformin, 100 µg/L guanylurea, or a mixture of both compounds, with samples collected over a 96-h time course to investigate potential impacts to the hepatic transcriptome or metabolome. Neither metformin nor guanylurea affected steroid production by ovary tissue exposed ex vivo. In the 23 days of exposure, neither compound significantly impacted transcription of endocrine-related genes in male liver or gonad, circulating steroid concentrations in either sex, or fecundity of spawning pairs. In the 96-h time course, 100 µg guanylurea/L elicited more differentially expressed genes than 41 µg metformin/L and showed the greatest impacts at 96 h. Hepatic transcriptome and metabolome changes were chemicaland time-dependent, with the largest impact on the metabolome observed at 23 days of exposure to 100 µg guanylurea/L. Overall, metformin and guanylurea did not elicit effects consistent with reproductive toxicity in adult fathead minnows at environmentally relevant concentrations.

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Effect of metformin on myotube BCAA catabolism

Cited by 22 publications

References 36 publications

Loss of the Drosophila branched-chain α-keto acid dehydrogenase complex (BCKDH) results in neuronal dysfunction

Loss of the Drosophila branched-chain α-keto acid dehydrogenase complex (BCKDH) results in neuronal dysfunction

PGC-1α-Targeted Therapeutic Approaches to Enhance Muscle Recovery in Aging

Effects of Metformin and its Metabolite Guanylurea on Fathead Minnow (Pimephales promelas) Reproduction

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