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The ability to maintain skeletal muscle mass appears to be impaired in insulin-resistant conditions, such as type 2 diabetes, that are characterized by muscle lipid accumulation. The current study investigated the effect of acutely increasing lipid availability on muscle protein synthesis. Seven healthy young male volunteers underwent a 7-h intravenous infusion of l-[ring-2H5]phenylalanine on two randomized occasions combined with 0.9% saline or 10% Intralipid at 100 mL/h. After a 4-h “basal” period, a 21-g bolus of amino acids was administered and a 3-h hyperinsulinemic-euglycemic clamp was commenced (“fed” period). Muscle biopsy specimens were obtained from the vastus lateralis at 1.5, 4, and 7 h. Lipid infusion reduced fed whole-body glucose disposal by 20%. Furthermore, whereas the mixed muscle fractional synthetic rate increased from the basal to the fed period during saline infusion by 2.2-fold, no change occurred during lipid infusion, despite similar circulating insulin and leucine concentrations. This “anabolic resistance” to insulin and amino acids with lipid infusion was associated with a complete suppression of muscle 4E-BP1 phosphorylation. We propose that increased muscle lipid availability may contribute to anabolic resistance in insulin-resistant conditions by impairing translation initiation.

Obesity is increasing, yet despite the necessity to maintain muscle mass and function with age, the effect of obesity on muscle protein turnover in older adults remains unknown. Eleven obese (BMI 31.9 ±1.1) and 15 healthy weight (HW; BMI 23.4 ±0.3) older men (55-75 years old) participated in a study that determined muscle protein synthesis (MPS) and leg protein breakdown (LPB) under post-absorptive (hypoinsulinaemic euglycaemic clamp) and post-prandial (hyperinsulinemic hyperaminoacidaemic euglycaemic clamp) conditions. Obesity was associated with systemic inflammation, greater leg fat mass, and patterns of mRNA expression consistent with muscle deconditioning, whilst leg lean mass, strength and work done during maximal exercise were no different. Under post-absorptive conditions, MPS and LPB were equivalent between groups, while insulin and amino acid administration increased MPS in only HW subjects and was associated with lower leg glucose disposal (LGD, 63%) in obese. Blunting of MPS in the obese was offset by an apparent decline in LPB, which was absent in HW subjects. Lower post-prandial LGD in obese subjects and blunting of MPS responses to amino acids suggests obesity in older adults is associated with diminished muscle metabolic quality. However this doesn’t appear to be associated with lower leg lean mass or strength.