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Individuals with a history of traumatic brain injury (TBI) are at increased risk for a number of disorders, including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. However, mediators of the long-term morbidity are uncertain. We conducted a multi-site, prospective trial in chronic TBI patients (∼18 years post-TBI) living in long-term 24-h care environments and local controls without a history of head injury. Inability to give informed consent was exclusionary for participation. A total of 41 individuals (17 moderate-severe TBI, 24 controls) were studied before and after consumption of a standardized breakfast to determine if concentrations of amino acids, cytokines, C-reactive protein, and insulin are potential mediators of long-term TBI morbidity. Analyte concentrations were measured in serum drawn before (fasting) and 1 h after meal consumption. Mean ages were 44 ± 15 and 49 ± 11 years for controls and chronic TBI patients, respectively. Chronic TBI patients had significantly lower circulating concentrations of numerous individual amino acids, as well as essential amino acids (p = 0.03) and large neutral amino acids (p = 0.003) considered as groups, and displayed fundamentally altered cytokine-amino acid relationships. Many years after injury, TBI patients exhibit abnormal metabolic responses and altered relationships between circulating amino acids, cytokines, and hormones. This pattern is consistent with TBI, inducing a chronic disease state in patients. Understanding the mechanisms causing the chronic disease state could lead to new treatments for its prevention.

The combination of increasing blood flow and amino acid (AA) availability provides an anabolic stimulus to the skeletal muscle of healthy young adults by optimizing both AA delivery and utilization. However, aging is associated with a blunted response to anabolic stimuli and may involve impairments in endothelial function. We investigated whether age-related differences exist in the muscle protein anabolic response to AAs between younger (30 ± 2 yr) and older (67 ± 2 yr) adults when macrovascular and microvascular leg blood flow were similarly increased with the nitric oxide (NO) donor, sodium nitroprusside (SNP). Regardless of age, SNP+AA induced similar increases above baseline (P ≤ 0.05) in macrovascular flow (4.3 vs. 4.4 ml·min(-1)·100 ml leg(-1) measured using indocyanine green dye dilution), microvascular flow (1.4 vs. 0.8 video intensity/s measured using contrast-enhanced ultrasound), phenylalanine net balance (59 vs. 68 nmol·min(-1)·100 ml·leg(-1)), fractional synthetic rate (0.02 vs. 0.02%/h), and model-derived muscle protein synthesis (62 vs. 49 nmol·min(-1)·100 ml·leg(-1)) in both younger vs. older individuals, respectively. Provision of AAs during NO-induced local skeletal muscle hyperemia stimulates skeletal muscle protein metabolism in older adults to a similar extent as in younger adults. Our results suggest that the aging vasculature is responsive to exogenous NO and that there is no age-related difference per se in AA-induced anabolism under such hyperemic conditions.

Purpose of Review: Cancer cachexia is associated with marked alterations in skeletal muscle protein metabolism that lead to muscle wasting and, in some cases, death. The inflammatory response elicited by cancer is a likely, if not primary, mediator of these alterations. This review focuses on the possible relationship between inflammatory signaling and altered amino acid metabolism in cancer., Recent Findings: Loss of skeletal muscle in cancer patients can potentially be due to anorexia and early satiety, reduced muscle protein synthesis, and/or increased muscle protein breakdown. Inflammation has been associated with each of these mechanisms. Effects on appetite appear to be mediated by the melanocortin system in the hypothalamus. Studies in animal models of cachexia suggest that modulation of orexigenic and anorexigenic pathways in this system may improve nutrient consumption. Inflammatory cytokines such as IL-6 and TNF-alpha are likely to contribute to the effects of inflammation on muscle protein metabolism through several pathways., Summary: Limited studies in humans suggest that targeted anti-inflammatory and nutritional interventions may ameliorate the net catabolic effect on skeletal muscle protein metabolism. Future studies of the precise mechanism of muscle protein loss, as well as novel or combination therapies to inhibit inflammation and promote anabolism, are warranted.

Age-related skeletal muscle loss is thought to stem from suboptimal nutrition and resistance to anabolic stimuli. Impaired microcirculatory (nutritive) blood flow may contribute to anabolic resistance by reducing delivery of amino acids to skeletal muscle. In this study, we employed contrast-enhanced ultrasound, microdialysis sampling of skeletal muscle interstitium, and stable isotope methodology, to assess hemodynamic and metabolic responses of older individuals to endurance type (walking) exercise during controlled amino acid provision. We hypothesized that older individuals would exhibit reduced microcirculatory blood flow, interstitial amino acid concentrations, and amino acid transport when compared with younger controls. We report for the first time that aging induces anabolic resistance following endurance exercise, manifested as reduced (by ~40%) efficiency of muscle protein synthesis. Despite lower (by ~40-45%) microcirculatory flow in the older than in the younger participants, circulating and interstitial amino acid concentrations and phenylalanine transport into skeletal muscle were all equal or higher in older individuals than in the young, comprehensively refuting our hypothesis that amino acid availability limits postexercise anabolism in older individuals. Our data point to alternative mediators of age-related anabolic resistance and importantly suggest correction of these impairments may reduce requirements for, and increase the efficacy of, dietary protein in older individuals. [ABSTRACT FROM AUTHOR]