Leucine increases mitochondrial metabolism and lipid content without altering insulin signaling in myotubes

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

doi:10.1016/j.biochi.2019.10.017

Cited by 28 publications

(29 citation statements)

References 52 publications

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“…Models of hyperinsulinemia have also been explored using cultured skeletal muscle cells. For example, insulin treatment in cultured muscle cells has led to a significant depression in p‐Akt expression during insulin stimulation (similar to our findings), suggesting successful induction of insulin resistance (Kumar & Dey, 2002, 2003; Lyon et al, 2019; Parry et al, 2020; Rivera, Lyon, Johnson, Sunderland, & Vaughan, 2020a; Rivera, Lyon, Johnson, & Vaughan, 2020b; Turner et al, 2018; Yang et al, 2012). Despite others having shown hyperinsulinemia reduced Ppargc1a mRNA expression (Yang et al, 2012), our report found no effect of hyperinsulinemia on Ppargc1a mRNA (which is consistent with other observations (Crunkhorn et al, 2007)).…”

Section: Discussionsupporting

confidence: 87%

“…Relevant references with experimental details include: 200–600 μM palmitate in BSA for 24 h (Yang et al, 2012), 200–600 μM palmitate in BSA for 24 h (Yang et al, 2013), 500 μM palmitate in BSA for 16 h (Coll et al, 2008), 500 μM palmitate in BSA for 4–16 h (Crunkhorn et al, 2007), 500 μM palmitate in BSA for 24–96 h (Bryner et al, 2012), 750 μM palmitate in BSA for 1–16 h (Coll et al, 2006), or 750 μM palmitate in BSA for up to 24 h (Haghani et al, 2015). A hyperinsulinemia condition (IR) was accomplished similarly to previous experiments by supplementing differentiation media with 100 nM insulin (Kumar & Dey, 2002; Kumar & Dey, 2003), which was replaced daily during the final 3 days of differentiation (control cells received differentiation media daily without added insulin) (Parry et al, 2020; Rivera, Lyon, Johnson, & Vaughan, 2020b). To investigate the potential additive effect of both stimuli on cell physiology, insulin resistance was induced as described above for 4 days, with the final 24 h including palmitate treatment at 500 μM in 0.1% ethanol with 2%BSA and 2%HS (PAM‐IR) with control cells receiving 0.1% ethanol with 2%BSA and 2%HS during the final day of treatment.…”

Section: Methodsmentioning

confidence: 99%

“…The treatment of myotubes with palmitate has been shown to increase TNFα expression and reduce insulin sensitivity and GLUT4 content (Jove et al, 2006). Similarly, excess insulin exposure has previously been shown to diminish insulin sensitivity in a variety of cell types including skeletal muscle (Kumar & Dey, 2002; Kumar & Dey, 2003; Lyon et al, 2019; Parry et al, 2020; Rivera, Lyon, Johnson, Sunderland, & Vaughan, 2020a; Rivera, Lyon, Johnson, & Vaughan, 2020b; Turner et al, 2018; Yang et al, 2012), and may be mediated through a downregulation of the insulin receptor (Kumar & Dey, 2003).…”

Section: Introductionmentioning

confidence: 93%

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Comparing the effects of palmitate, insulin, and palmitate‐insulin co‐treatment on myotube metabolism and insulin resistance

Rivera

Vaughan

2021

Lipids

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Previous studies have shown various metabolic stressors such as saturated fatty acids (SFA) and excess insulin promote insulin resistance in metabolically meaningful cell types (such as skeletal muscle). Additionally, these stressors have been linked with suppressed mitochondrial metabolism, which is also a common characteristic of skeletal muscle of diabetics. This study characterized the individual and combined effects of excess lipid and excess insulin on myotube metabolism and related metabolic gene and protein expression. C2C12 myotubes were treated with either 500 μM palmitate (PAM), 100 nM insulin (IR), or both (PAM‐IR). qRT‐PCR and western blot were used to measure metabolic gene and protein expression, respectively. Oxygen consumption was used to measure mitochondrial metabolism. Glycolytic metabolism and insulin‐mediated glucose uptake were measured via extracellular acidification rate. Cellular lipid and mitochondrial content were measured using Nile Red and NAO staining, respectively. IR and PAM‐IR treatments led to reductions in p‐Akt expression. IR treatment reduced insulin mediated glucose metabolism while PAM and PAM‐IR treatment showed increases with concurrent reductions in mitochondrial metabolism. All three treatments showed suppression in mitochondrial metabolism. PAM and PAM‐IR also showed increases in glycolytic metabolism. While PAM and PAM‐IR significantly increased lipid content, expression of inflammatory and lipogenic proteins were unaltered. Lastly, PAM‐IR reduced BCAT2 protein expression, a regulator of BCAA metabolism. Both stressors independently reduced insulin signaling, mitochondrial function, and cell metabolism, however, only PAM‐IR co‐treatment significantly reduced the expression of regulators of metabolism not seen with individual stressors, suggesting an additive effect of stressors on metabolic programming.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Comparing the effects of palmitate, insulin, and palmitate‐insulin co‐treatment on myotube metabolism and insulin resistance

Rivera

Vaughan

2021

Lipids

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“…BCAA are associated with gut flora metabolism. To support this connection, mice receiving fecal microbiome from the obese twins displayed substantial increases in serum BCAA concentrations (Ridaura et al 2013). Among human gut microbial species mainly Prevotella, Streptococcus and Bacteroides biosynthesize BCAA (Pedersen et al 2016;Yue et al 2019).…”

Section: Bcaa Deprivationmentioning

confidence: 99%

Branched chain amino acids—friend or foe in the control of energy substrate turnover and insulin sensitivity?

Supruniuk

Żebrowska

Chabowski

2021

Critical Reviews in Food Science and Nutrition

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Branched chain amino acids (BCAA) and their derivatives are bioactive molecules with pleiotropic functions in the human body. elevated fasting blood BCAA concentrations are considered as a metabolic hallmark of obesity, insulin resistance, dyslipidaemia, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease. However, since increased BCAA amount is observed both in metabolically healthy and obese subjects, a question whether BCAA are mechanistic drivers of insulin resistance and its morbidities or only markers of metabolic dysregulation, still remains open. The beneficial effects of BCAA on body weight and composition, aerobic capacity, insulin secretion and sensitivity demand high catabolic potential toward amino acids and/or adequate BCAA intake. On the opposite, BCAA-related inhibition of lipogenesis and lipolysis enhancement may preclude impairment in insulin sensitivity. Thereby, the following review addresses various strategies pertaining to the modulation of BCAA catabolism and the possible roles of BCAA in energy homeostasis. we also aim to elucidate mechanisms behind the heterogeneity of ramifications associated with BCAA modulation.

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“…The branch-chained amino acid (BCAA) leucine is well known to activate mechanistic target of rapamycin complex 1 (mTORC1) and promote muscle protein synthesis [ 49 , 50 ]. Leucine has also been shown to stimulate the SIRT1–AMPKα–PGC-1α signaling axis in skeletal muscle cells [ 51 , 52 , 53 , 54 , 55 ]. Though leucine treatment is not fully effective against muscle atrophy during disuse in rodents and humans [ 56 , 57 , 58 ], the role of leucine to enhance muscle recovery is a far less studied context.…”

Section: Potential Nutritional Therapiesmentioning

confidence: 99%

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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Leucine increases mitochondrial metabolism and lipid content without altering insulin signaling in myotubes

Cited by 28 publications

References 52 publications

Comparing the effects of palmitate, insulin, and palmitate‐insulin co‐treatment on myotube metabolism and insulin resistance

Comparing the effects of palmitate, insulin, and palmitate‐insulin co‐treatment on myotube metabolism and insulin resistance

Branched chain amino acids—friend or foe in the control of energy substrate turnover and insulin sensitivity?

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

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