The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTor signaling in vivo and the expression of myogenic genes in vitro

Abstract

Objectives Nutrition plays a key role in the maintenance of muscle and bone mass, and dietary protein deficiency has in particular been associated with catabolism of both muscle and bone tissue. One mechanism thought to link protein deficiency with loss of muscle mass is deficiency in specific amino acids that play a role in muscle metabolism. We tested the hypothesis that the essential amino acid tryptophan, and its metabolite kynurenine, might directly impact muscle metabolism in the setting of protein deficiency. Methods Adult mice (12 mo) were fed a normal diet (18% protein), as well as diets with low protein (8%) supplemented with increasing concentrations (50, 100, and 200 uM) of kynurenine (Kyn; or with tryptophan (Trp; 1.5 mM). Myoprogenitor cells were also treated with Trp and Kyn in vitro to determine their effects on cell proliferation and expression of myogenic differentiation markers. Results Results indicate that all mice on the low protein diets weighed less than the group fed normal protein (18%). Lean mass measured by DXA was lowest in mice on the high kynurenine diet, whereas percent lean mass was highest in mice receiving tryptophan supplementation and percent body fat was lowest in mice receiving tryptophan. ELISA assays showed significant increases in skeletal muscle IGF-1, leptin, and the myostatin antagonist follistatin with tryptophan supplementation. mRNA microarray and gene pathway analysis performed on muscle samples demonstrate that mTor/eif4/p70s6k pathway molecules are significantly up-regulated in muscles from mice on Kyn and Trp supplementation. In vitro, neither amino acid affected proliferation of myoprogenitors, but tryptophan increased the expression of the myogenic markers MyoD, myogenin, and myosin heavy chain. Conclusion Together, these findings suggest that dietary amino acids can directly impact molecular signaling in skeletal muscle, further indicating that dietary manipulation with specific amino acids could potentially attenuate muscle loss with dietary protein deficiency.

Low Levels of Serum Tryptophan Underlie Skeletal Muscle Atrophy

“…When intracellular amino acid levels begin to fall, amino acid-sensing pathways reduce protein synthesis to maintain viable intracellular amino acid concentrations [21]. Recent evidence suggests that the mTOR complex 1 amino acid-sensing pathway [21] contributes to the reduction of protein synthesis and, ultimately, to atrophy of aged skeletal muscles [30]. Our analysis of the metabolome of skeletal muscles from the mice fed the Trp-deficient diet showed a clear reduction in glycolysis.…”

“…Our data also indicated a negative correlation between serum levels of Trp and myostatin. Trp supplementation causes significant increases in the skeletal muscle levels of insulin-like growth factor-1, leptin, and follistatin, which is a myostatin antagonist [30].…”

Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome

“…Disruption of tryptophan metabolism may also contribute to steroid-dependent skeletal muscle alteration. Given that tryptophan and its metabolite kynurenine have shown positive effects on the expression of myogenic markers in animal models (17), reduced levels of those compounds may represent a pejorative factor contributing to cortisol-induced reduction of protein synthesis. Due to its ability to cross the blood-brain barrier (18), lower plasma tryptophan levels may also be associated with a reduced intracerebral serotonin production.…”

Aging Gut Microbiota at the Cross-Road between Nutrition, Physical Frailty, and Sarcopenia: Is There a Gut–Muscle Axis?

“…Moreover, the gut microbiota is able to synthesize some amino acids, such as tryptophan, representing the fundamental substrates for muscle protein anabolism [ 108 ]. Tryptophan may also stimulate the IGF-1/p70s6k/mTor pathway in muscle cells, promoting the expression of genes involved in myofibrillar synthesis [ 109 ]. Betaine, a microbial metabolite derived by glycine betaine provided by diet, can activate cytosolic calcium influx, Extracellular-signal–Regulated Kinase (ERK) signaling, and IGF-1 synthesis in human osteoblast cultures, which enables hypothesizing its effect on skeletal muscle cells [ 110 ].…”