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 of maintaining 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 kg · m−2) and 15 healthy-weight (BMI 23.4 ± 0.3 kg · m−2) older men (55–75 years old) participated in a study that determined muscle protein synthesis (MPS) and leg protein breakdown (LPB) under postabsorptive (hypoinsulinemic-euglycemic clamp) and postprandial (hyperinsulinemic hyperaminoacidemic-euglycemic clamp) conditions. Obesity was associated with systemic inflammation, greater leg fat mass, and patterns of mRNA expression consistent with muscle deconditioning, whereas leg lean mass, strength, and work done during maximal exercise were no different. Under postabsorptive conditions, MPS and LPB were equivalent between groups, whereas insulin and amino acid administration increased MPS in only healthy-weight subjects and was associated with lower leg glucose disposal (LGD) (63%) in obese men. Blunting of MPS in the obese men was offset by an apparent decline in LPB, which was absent in healthy-weight subjects. Lower postprandial LGD in obese subjects and blunting of MPS responses to amino acids suggest that obesity in older adults is associated with diminished muscle metabolic quality. This does not, however, appear to be associated with lower leg lean mass or strength.

Muscle mass loss accompanies periods of bedrest and limb immobilization in humans and requires rehabilitation exercise to effectively restore mass and function. Although recent evidence points to an early and transient rise in muscle protein breakdown contributing to this decline in muscle mass, the driving factor seems to be a reduction in muscle protein synthesis, not least in part due to the development of anabolic resistance to amino acid provision. Although the AKT signaling pathway has been identified in small animals as central to the regulation of muscle protein synthesis, several studies in humans have now demonstrated a disassociation between AKT signaling and muscle protein synthesis during feeding, exercise, and immobilization, suggesting that the mechanisms regulating protein synthesis in human skeletal muscle are more complex than initially thought (at least in non-inflammatory states). During rehabilitation, exercise-induced myogenesis may in part be responsible for the recovery of muscle mass. Rapid and sustained exercise-induced suppression of myostatin mRNA expression, that precedes any gain in muscle mass, points to this, along with other myogenic proteins, as being potential regulators of muscle regeneration during exercise rehabilitation in humans.

The underlying aetiology of sarcopenia appears multifaceted and not yet fully defined, but ultimately involves the gradual loss of muscle protein content over time. The present evidence suggests that the loss of lean tissue in the elderly is exacerbated by low dietary protein intake. Moreover, acute stable-isotope-based methodologies have demonstrated that the muscle anabolic response to a given amount of protein may decline with age, a phenomenon that has been termed anabolic resistance. Although the mechanism responsible for the inability of muscle to mount a satisfactory anabolic response to protein provision with increasing age is presently unknown, it does not appear due to impaired digestion or absorption of dietary protein. Rather, the issue could reside with any combination of: a diminished delivery of amino acids to peripheral tissues, impaired uptake of amino acids into muscle cells, or an inability of amino acids to elicit intracellular events pivotal for anabolism to occur. Despite the presence of anabolic resistance to dietary protein, present evidence suggests that protein supplementation may be able to overcome these issues, particularly when combined with resistance exercise programmes. As such, protein supplementation may prove to be an effective approach to delay the loss of muscle mass with age and has led to calls for the recommended daily intake of protein to be increased for the elderly population.

We sought to ascertain the time course of transcriptional events that occur in human skeletal muscle at the outset of resistance exercise (RE) training in RE naive individuals and determine whether the magnitude of response was associated with exercise-induced muscle damage. Sixteen RE naive men were recruited; eight underwent two sessions of 5 × 30 maximum isokinetic knee extensions (180°/s) separated by 48 h. Muscle biopsies of the vastus lateralis, obtained from different sites, were taken at baseline and 24 h after each exercise bout. Eight individuals acted as nonexercise controls with biopsies obtained at the same time intervals. Transcriptional changes were assessed by microarray and protein levels of heat shock protein (HSP) 27 and αB-crystallin in muscle cross sections by immunohistochemistry as a proxy measure of muscle damage. In control subjects, no probe sets were significantly altered (false discovery rate < 0.05), and HSP27 and αB-crystallin protein remained unchanged throughout the study. In exercised subjects, significant intersubject variability following the initial RE bout was observed in the muscle transcriptome, with greatest changes occurring in subjects with elevated HSP27 and αB-crystallin protein. Following the second bout, the transcriptome response was more consistent, revealing a cohort of probe sets associated with immune activation, the suppression of oxidative metabolism, and ubiquitination, as differentially regulated. The results reveal that the initial transcriptional response to RE is variable in RE naive volunteers, potentially associated with muscle damage and unlikely to reflect longer term adaptations to RE training. These results highlight the importance of considering multiple time points when determining the transcriptional response to RE and associated physiological adaptation.