Abstract
Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m2) and lean (BMI, 22±1 kg/m2) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P<0.05). We then evaluated these same responses in a primary cell culture model, and tested the specific hypothesis that circulating non-esterified fatty acids (NEFA) in obesity play a role in the responses observed in humans. The findings on total protein synthesis and translation efficiency of β-F1-ATPase in primary myotubes cultured from a lean subject, and after exposure to NEFA extracted from serum of an obese subject, were similar to those obtained in humans. Among candidate microRNAs (i.e., non-coding RNAs regulating gene expression), we identified miR-127-5p in preventing the production of β-F1-ATPase. Muscle expression of miR-127-5p negatively correlated with β-F1-ATPase protein translation efficiency in humans (r = – 0.6744; P<0.01), and could be modeled in vitro by prolonged exposure of primary myotubes derived from the lean subject to NEFA extracted from the obese subject. On the other hand, locked nucleic acid inhibitor synthesized to target miR-127-5p significantly increased β-F1-ATPase translation efficiency in myotubes (0.6±0.1 vs 1.3±0.3, in control vs exposure to 50 nM inhibitor; P<0.05). Our experiments implicate circulating NEFA in obesity in suppressing muscle protein metabolism, and establish impaired β-F1-ATPase translation as an important consequence of obesity.
Highlights
The increasing prevalence of obesity is a major health concern due to its associated physiological and metabolic consequences
We have shown that acute increase in plasma non-esterified fatty acid (NEFA) availability induced by the intravenous infusion of a fat emulsion, it induced insulin resistance, did not impair the muscle anabolic response to amino acids [6], which suggests disassociation between NEFA-mediated insulin resistance and muscle protein metabolism
Because generally polyunsaturated fatty acids (PUFA), or arachidonic acid [38,39] have been linked to favorable effects on muscle protein metabolism, NEFA were extracted from the serum of a lean subject with relatively higher PUFA concentrations and PUFA/saturated fatty acids (SFA) ratio among the lean subjects (i.e., Lean NEFA(P))
Summary
The increasing prevalence of obesity is a major health concern due to its associated physiological and metabolic consequences. It is possible that fatty acids, either directly or indirectly via their effects on inducing insulin resistance, may reduce protein synthesis in muscle in obesity. In an animal model of dietary fat-induced obesity, reduced muscle protein synthesis is observed concomitant with increased lipid infiltration in muscle [8]. Taken together, the latter evidence suggests that muscle lipid exposure, which can be either through plasma NEFA or via the action of lipoprotein lipase in circulating triacylglycerols, or triacylglycerol-associated fatty acids from adipocytes interspersed between muscle fibers, can impair muscle protein metabolism in the setting of obesity
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