Metabolites related to renal function, immune activation, and carbamylation are associated with muscle composition in older adults

Abstract

Reduced skeletal muscle density in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of skeletal muscle density, we conducted a secondary analysis of previously published muscle composition and serum metabolomic data in 73 older adults (average age, 78y). Multivariable-adjusted linear regression was used to examine associations between 321 metabolites with muscle composition, defined as the ratio between normal density (NDM) with low density (LDM) thigh muscle cross sectional area (NDM/LDM). Sixty metabolites were significantly (p≤0.05 and q<0.30) associated with NDM/LDM. Decreased renal function and the immune response have been previously linked with reduced muscle density, but the mechanisms underlying these connections are less clear. Metabolites that were significantly associated with muscle composition were then tested for their association with circulating markers of renal function (blood urea nitrogen, creatinine, uric acid), and with the immune response (neutrophils/lymphocytes) and activation (kynurenine/tryptophan). 43 significant NDM/LDM metabolites (including urea) were co-associated with at least 1 marker of renal function; 23 of these metabolites have been previously identified as uremic solutes. The neutrophil/lymphocyte ratio was significantly associated with NDM/LDM (β±SE: -0.3±0.1, p=0.01, q=0.04). 35 significant NDM/LDM metabolites were co-associated with immune activation. Carbamylation (defined as homocitrulline/lysine) was identified as a pathway that may link renal function and immune activation with muscle composition, as 29 significant NDM/LDM metabolites were co-associated with homocitrulline/lysine, with at least 2 markers of renal function, and with kynurenine/tryptophan. When considering that elevated urea and uremic metabolites have been linked with an increased systemic microbial burden, that antimicrobial defense can be reduced in the presence of carbamylation, and that adipocytes can promote host defense, we propose the novel hypothesis that the age-related increase in adipogenesis within muscle may be a compensatory antimicrobial response to protect against an elevated microbial burden.

Muscle strength is increased in mice that are colonized with microbiota from high-functioning older adults

“…Statistical significance for between-group differences in taxonomy or functions was set at a p-value ≤ 0.05 and the false discovery rate at (FDR) ≤ 0.30. A FDR of 0.30 indicates that the result is likely to be valid 7 out of 10 times, which we suggest is reasonable in the setting of exploratory discovery (Lustgarten and Fielding, 2017).…”

The relationship between blood metabolites of the tryptophan pathway and kidney function: a bidirectional Mendelian randomization analysis

“…In a previous association study, higher levels of indole-3-lactate were found to be cross-sectionally associated with lower eGFR 16 . In an elderly population, indole-3-lactate was found to be associated not only with muscle composition but also with the renal function markers serum creatinine and blood urea nitrogen 78 . Quite recently, a study group reported that increased levels of indole-3-lactate were found to be associated with lower eGFR in a cohort of patients with ADPKD 79 .…”

Serum metabolites associate with physical performance among middle-aged adults: Evidence from the Bogalusa Heart Study

“…One theory on the relation between kidney function and physical performance is that this accumulation of small molecules has a detrimental effect on other systems in the body [ 40 ], including those that govern physical performance – that declines in kidney function lead to declines in physical performance through serum metabolites. In support of this theory, two recent papers posit a relation between declines in kidney function and sarcopenia through serum metabolites [ 41 , 42 ]; however, the extent to which these findings apply to other physical performance measures is unclear. An alternative theory is that declines in kidney function and declines in physical performance are both governed by a common ‘accelerated aging’ phenotype [ 38 ], and that identified common metabolites may be markers of accelerated aging.…”