Molecular insight and pharmacological approaches targeting mitochondrial dynamics in skeletal muscle during obesity

2015 ◽  
Vol 1350 (1) ◽  
pp. 82-94 ◽  
Author(s):  
Huei-Fen Jheng ◽  
Shin-Han Huang ◽  
Hsueh-Maio Kuo ◽  
Michael W. Hughes ◽  
Yau-Sheng Tsai
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dynamics

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

2012 ◽  
Vol 302 (6) ◽  
pp. E731-E739 ◽  
Author(s):  
Maria H. Holmström ◽  
Eduardo Iglesias-Gutierrez ◽  
Juleen R. Zierath ◽  
Pablo M. Garcia-Roves
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Respiratory Capacity ◽  
Tissue Specific ◽  
Mitochondrial Respiratory

The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/ ?) and obese diabetic ( db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction.

scholarly journals Decreased Mitochondrial Dynamics Is Associated with Insulin Resistance, Metabolic Rate, and Fitness in African Americans

2019 ◽  
Vol 105 (4) ◽  
pp. 1210-1220 ◽  
Author(s):  
John J Dubé ◽  
Michael L Collyer ◽  
Sara Trant ◽  
Frederico G S Toledo ◽  
Bret H Goodpaster ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Metabolic Rate ◽  
African American Women ◽  
Racial Differences ◽  
Mitochondrial Dynamics ◽  
Resting Metabolic Rate ◽  
Gene Array ◽  
Mitochondrial Capacity

Abstract Context African American women (AAW) have a higher incidence of insulin resistance and are at a greater risk for the development of obesity and type 2 diabetes than Caucasian women (CW). Although several factors have been proposed to mediate these racial disparities, the mechanisms remain poorly defined. We previously demonstrated that sedentary lean AAW have lower peripheral insulin sensitivity, reduced maximal aerobic fitness (VO2max), and lower resting metabolic rate (RMR) than CW. We have also demonstrated that skeletal muscle mitochondrial respiration is lower in AAW and appears to play a role in these racial differences. Objective The goal of this study was to assess mitochondrial pathways and dynamics to examine the potential mechanisms of lower insulin sensitivity, RMR, VO2max, and mitochondrial capacity in AAW. Design To achieve this goal, we assessed several mitochondrial pathways in skeletal muscle using gene array technology and semiquantitative protein analysis. Results We report alterations in mitochondrial pathways associated with inner membrane small molecule transport genes, fusion–fission, and autophagy in lean AAW. These differences were associated with lower insulin sensitivity, RMR, and VO2max. Conclusions Together these data suggest that the metabolic racial disparity of insulin resistance, RMR, VO2max, and mitochondrial capacity may be mediated by perturbations in mitochondrial pathways associated with membrane transport, fission–fusion, and autophagy. The mechanisms contributing to these differences remain unknown.

scholarly journals Eicosapentaenoic Acid-Induced Inhibition of Metabolic Inflammation Is Associated with Preserved Mitochondrial Function and Insulin Sensitivity in Human Primary Myotubes

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 471-471
Author(s):  
Domenico Sergi ◽  
Natalie Luscombe-Marsh ◽  
Leonie Kaye Heilbronn ◽  
Mark Birch-Machin ◽  
Christopher Proud ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Eicosapentaenoic Acid ◽  
Mitochondrial Function ◽  
Core Protein ◽  
Mitochondrial Dynamics ◽  
Complex Iii ◽  
Nuclear Factor ◽  
Metabolic Inflammation ◽  
Nuclear Factor Kappa

Abstract Objectives The aim of this study was to investigate whether metabolic inflammation in skeletal muscle may be prevented by eicosapentaenoic acid (EPA) and if this is associated with an improvement in markers of mitochondrial function and insulin sensitivity. Methods Human primary myotubes were treated for 24 hours with palmitic acid (PA, 500 µM) in hyperglycaemic conditions (13 mM glucose), referred to as nutrient overload, in the presence or absence of EPA (100 µM). After the treatments, the expression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC1α) and interleukin-6 (IL-6) was assessed by q-PCR. Western blot was used to asses the abundance of the inhibitor of nuclear factor kappa-B (IKBα), mitochondrial electron transport chain complex proteins, the phosphorylation of AKT (Ser473) and AKT substrate 160 (AS 160) (Thr642) in response to insulin, the activation of 5'-AMP-activated protein kinase (AMPK) and the inhibition of acetyl-CoA carboxylase (ACC). Mitochondrial dynamics was assessed by immunocytochemistry. Results Nutrient excess activated the proinflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) signalling as indicated by the upregulation of IL-6 mRNA (P < 0.001) and a tendency to decrease in IKBα (P = 0.0654), tended to downregulate PGC1α (P = 0.0589) and promoted mitochondrial fragmentation (P < 0.001), all of which were counteracted by EPA. Furthermore, EPA induced complex III-core protein 2 (P < 0.05) relative to control cells, an effect that was absent in the myotubes exposed only to PA and hyperglycaemia. EPA, when administrated in combination with PA and hyperglycaemia, induced the phosphorylation of AMPK (P < 0.05) and its downstream target ACC (P < 0.05) relative to cells exposed to nutrient overload alone. Finally, while fuel surplus impaired insulin-induced phosphorylation of AKT (P < 0.01) and AS160 (P < 0.05), these effects were prevented by EPA. Conclusions EPA inhibited NFkB signalling which was associated with an attenuation of the deleterious effects of PA and hyperglycaemia on markers of mitochondrial function and insulin sensitivity. Thus, EPA may represent a valuable nutritional tool to preserve skeletal muscle mitochondrial function and metabolic health during periods of nutrient overload. Funding Sources CSIRO's Precision Health Future Science Platform (FSP).

scholarly journals Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity

Diabetologia ◽  
2020 ◽  
Author(s):  
Alexandre Houzelle ◽  
Johanna A. Jörgensen ◽  
Gert Schaart ◽  
Sabine Daemen ◽  
Nynke van Polanen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Quality Control ◽  
Insulin Sensitivity ◽  
Aerobic Capacity ◽  
Mitochondrial Dynamics ◽  
Oxidative Capacity ◽  
Protein Balance ◽  
Diabetes Patients

Abstract Aims/hypothesis Mitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity. Methods In a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue. Results Type 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 ± 4.0 and 56.7 ± 7.2 vs 21.8 ± 2.5 and 25.1 ± 4.3 years, p < 0.001, respectively) and displayed a higher BMI (32.4 ± 3.7 and 31.0 ± 3.7 vs 22.1 ± 1.8 and 21.0 ± 1.5 kg/m2, p < 0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 ± 0.79 vs 0.79 ± 0.51 AU, p = 0.002; and OPA1: 1.55 ± 0.64 vs 0.76 ± 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p < 0.001 and r = 0.61, p < 0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively). Conclusions/interpretation Collectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity. Clinical Trial registry numbers NCT00943059, NCT01298375 and NL1888

scholarly journals Effect of electrical stimulation-induced resistance exercise on mitochondrial fission and fusion proteins in rat skeletal muscle

2015 ◽  
Vol 40 (11) ◽  
pp. 1137-1142 ◽  
Author(s):  
Yu Kitaoka ◽  
Riki Ogasawara ◽  
Yuki Tamura ◽  
Satoshi Fujita ◽  
Hideo Hatta
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Resistance Exercise ◽  
Mitochondrial Function ◽  
Muscle Protein ◽  
Mitochondrial Dynamics ◽  
Muscle Protein Synthesis ◽  
Mitochondrial Fission ◽  
Dynamic Networks ◽  
Rat Skeletal Muscle

It is well known that resistance exercise increases muscle protein synthesis and muscle strength. However, little is known about the effect of resistance exercise on mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria exist as dynamic networks that are continuously remodeling through fusion and fission. The purpose of this study was to investigate the effect of acute and chronic resistance exercise, which induces muscle hypertrophy, on the expression of proteins related to mitochondrial dynamics in rat skeletal muscle. Resistance exercise consisted of maximum isometric contraction, which was induced by percutaneous electrical stimulation of the gastrocnemius muscle. Our results revealed no change in levels of proteins that regulate mitochondrial fission (Fis1 and Drp1) or fusion (Opa1, Mfn1, and Mfn2) over the 24-h period following acute resistance exercise. Phosphorylation of Drp1 at Ser616 was increased immediately after exercise (P < 0.01). Four weeks of resistance training (3 times/week) increased Mfn1 (P < 0.01), Mfn2 (P < 0.05), and Opa1 (P < 0.01) protein levels without altering mitochondrial oxidative phosphorylation proteins. These observations suggest that resistance exercise has little effect on mitochondrial biogenesis but alters the expression of proteins involved in mitochondrial fusion and fission, which may contribute to mitochondrial quality control and improved mitochondrial function.

Sign in / Sign up

Export Citation Format

Share Document