Mitochondrial ATP synthase β-subunit production rate and ATP synthase specific activity are reduced in skeletal muscle of humans with obesity.

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FINDINGS: What is the central question of this study? Humans with obesity have lower ATP synthesis in muscle along with lower content of the β-subunit of the ATP synthase (β-F1-ATPase), the catalytic component of the ATP synthase. Does lower synthesis rate of β-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 β-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. ABSTRACT: The content of the β-subunit of the ATP synthase (β-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 β-F1 -ATPase, as well as the specific activity of the ATP synthase. FSR of β-F1 -ATPase was determined using a combination of isotope tracer infusion and muscle biopsies. Gene expression of β-F1 -ATPase and specific activity of the ATP synthase were determined in the muscle biopsies. When compared to lean, obese subjects had lower muscle β-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 β-F1 -ATPase correlated with the FSR of β-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 β-F1 -ATPase content (P > 0.05). Obesity impairs the synthesis of β-F1 -ATPase in muscle at the translational level, reducing the content of β-F1 -ATPase in parallel with reduced capacity for ATP generation via the ATP synthase complex.