The impact of short-term forearm immobilization and acipimox administration on muscle amino acid metabolism and insulin sensitivity in healthy, young volunteers.

The mechanisms underpinning short-term muscle disuse atrophy remain to be elucidated, but perturbations in lipid metabolism may be involved. Specifically, positive muscle non-esterified fatty acid (NEFA) balance has been implicated in the development of disuse-induced insulin and anabolic resistance. Our aim was to determine the impact of acipimox administration (i.e. pharmacologically lowering circulating NEFA availability) on muscle amino acid metabolism and insulin sensitivity during short-term disuse. Eighteen healthy individuals (age 22±1 years, BMI 24.0±0.6 kg·m) underwent 2 days of forearm cast immobilization with placebo (PLA; =9, 5M/4F) or acipimox (ACI; 250 mg Olbetam; =9, 4M/5F) ingestion four times daily. Before and after immobilization, whole-body glucose disposal rate (GDR), forearm glucose uptake (FGU, i.e. muscle insulin sensitivity), and amino acid kinetics were measured under fasting and hyperinsulinaemic-hyperaminoacidaemic-euglycaemic clamp conditions using arteriovenous forearm balance and intravenous L-[-H]phenylalanine infusions. Immobilization did not affect GDR but decreased insulin-stimulated FGU in both groups, but to a greater degree in ACI (from 53±8 to 12±5 μmol·min) than in PLA (from 52±8 to 38±13 μmol·min; <0.05). In ACI only, fasting arterialised NEFA concentrations were elevated to 1.3±0.1 mmol·L post-immobilization (<0.05), and fasting forearm NEFA balance increased ~4-fold (=0.10). Forearm phenylalanine net balance tended to decrease following immobilization (<0.10), driven by increases in phenylalanine rates of appearance (from 32±5 (fasting) and 21±4 (clamp) pre-immobilization to 53±8 and 31±4 post-immobilization; <0.05) while rates of disappearance were unaffected and no effects of acipimox observed. Altogether, we show disuse-induced insulin resistance is accompanied by early signs of negative net muscle amino acid balance, which is driven by accelerated muscle amino acid efflux. Acutely elevated NEFA availability worsened muscle insulin resistance without affecting muscle amino acid kinetics, suggesting that disuse-associated increased muscle NEFA uptake may contribute to inactivity-induced insulin resistance but does not represent an early mechanism causing anabolic resistance.