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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]

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