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Mitochondrial H+-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance.

ABSTRACT: AIMS/HYPOTHESIS:Mitochondria are important regulators of the metabolic phenotype in type 2 diabetes. A key factor in mitochondrial physiology is the H+-ATP synthase. The expression and activity of its physiological inhibitor, ATPase inhibitory factor 1 (IF1), controls tissue homeostasis, metabolic reprogramming and signalling. We aimed to characterise the putative role of IF1 in mediating skeletal muscle metabolism in obesity and diabetes. METHODS:We examined the 'mitochondrial signature' of obesity and type 2 diabetes in a cohort of 100 metabolically characterised human skeletal muscle biopsy samples. The expression and activity of H+-ATP synthase, IF1 and key mitochondrial proteins were characterised, including their association with BMI, fasting plasma insulin, fasting plasma glucose and HOMA-IR. IF1 was also overexpressed in primary cultures of human myotubes derived from the same biopsies to unveil the possible role played by the pathological inhibition of the H+-ATP synthase in skeletal muscle. RESULTS:The results indicate that type 2 diabetes and obesity act via different mechanisms to impair H+-ATP synthase activity in human skeletal muscle (76% reduction in its catalytic subunit vs 280% increase in IF1 expression, respectively) and unveil a new pathway by which IF1 influences lipid metabolism. Mechanistically, IF1 altered cellular levels of ?-ketoglutarate and L-carnitine metabolism in the myotubes of obese (84% of control) and diabetic (76% of control) individuals, leading to limited ?-oxidation of fatty acids (60% of control) and their cytosolic accumulation (164% of control). These events led to enhanced release of TNF-? (10 ± 2 pg/ml, 27 ± 5 pg/ml and 35 ± 4 pg/ml in control, obese and type 2 diabetic participants, respectively), which probably contributes to an insulin resistant phenotype. CONCLUSIONS/INTERPRETATION:Overall, our data highlight IF1 as a novel regulator of lipid metabolism and metabolic disorders, and a possible target for therapeutic intervention.

SUBMITTER: Formentini L

PROVIDER: S-EPMC6572787 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Mitochondrial H<sup>+</sup>-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance.

Formentini Laura L Ryan Alexander J AJ Gálvez-Santisteban Manuel M Carter Leslie L Taub Pam P Lapek John D JD Gonzalez David J DJ Villarreal Francisco F Ciaraldi Theodore P TP Cuezva José M JM Henry Robert R RR

Diabetologia 20170802 10

<h4>Aims/hypothesis</h4>Mitochondria are important regulators of the metabolic phenotype in type 2 diabetes. A key factor in mitochondrial physiology is the H<sup>+</sup>-ATP synthase. The expression and activity of its physiological inhibitor, ATPase inhibitory factor 1 (IF1), controls tissue homeostasis, metabolic reprogramming and signalling. We aimed to characterise the putative role of IF1 in mediating skeletal muscle metabolism in obesity and diabetes.<h4>Methods</h4>We examined the 'mitoc ...[more]

PMID: 28770317

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Project description:New findingsWhat is the central question of this study? Humans with obesity have lower ATP synthesis in muscle along with lower content of the ?-subunit of the ATP synthase (?-F1-ATPase), the catalytic component of the ATP synthase. Does lower synthesis rate of ?-F1-ATPase in muscle contribute to these responses in humans with obesity? What is the main finding and its importance? Humans with obesity have a lower synthesis rate of ?-F1 -ATPase and ATP synthase specific activity in muscle. These findings indicate that reduced production of subunits forming the ATP synthase in muscle may contribute to impaired generation of ATP in obesity.AbstractThe content of the ?-subunit of the ATP synthase (?-F1 -ATPase), which forms the catalytic site of the enzyme ATP synthase, is reduced in muscle of obese humans, along with a reduced capacity for ATP synthesis. We studied 18 young (37 ± 8 years) subjects of which nine were lean (BMI = 23 ± 2 kg m-2 ) and nine were obese (BMI = 34 ± 3 kg m-2 ) to determine the fractional synthesis rate (FSR) and gene expression of ?-F1 -ATPase, as well as the specific activity of the ATP synthase. FSR of ?-F1 -ATPase was determined using a combination of isotope tracer infusion and muscle biopsies. Gene expression of ?-F1 -ATPase and specific activity of the ATP synthase were determined in the muscle biopsies. When compared to lean, obese subjects had lower muscle ?-F1 -ATPase FSR (0.10 ± 0.05 vs. 0.06 ± 0.03% h-1 ; P < 0.05) and protein expression (P < 0.05), but not mRNA expression (P > 0.05). Across subjects, abundance of ?-F1 -ATPase correlated with the FSR of ?-F1 -ATPase (P < 0.05). The specific activity of muscle ATP synthase was lower in obese compared to lean subjects (0.035 ± 0.004 vs. 0.042 ± 0.007 arbitrary units; P < 0.05), but this difference was not significant after the activity of the ATP synthase was adjusted to the ?-F1 -ATPase content (P > 0.05). Obesity impairs the synthesis of ?-F1 -ATPase in muscle at the translational level, reducing the content of ?-F1 -ATPase in parallel with reduced capacity for ATP generation via the ATP synthase complex.

Project description:Aims/hypothesisMitochondria 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.MethodsIn 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.ResultsType 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/interpretationCollectively, 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 Graphical abstract.

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Mitochondrial H+-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance.

Publications

Mitochondrial H<sup>+</sup>-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance.

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