Lean Body Mass Harbors Sensing Mechanisms that Allow Safeguarding of Methionine Homeostasis.

Yves Ingenbleek

doi:10.3390/nu9091035

Abstract

Protein-depleted states generate allosteric inhibition of liver cystathionine β-synthase (CBS), which governs the first enzymatic step of the transsulfuration cascade, resulting in upstream accretion of homocysteine (Hcy) in body fluids. A similar Hcy increase may arise from normal hepatocytes undergoing experimentally-induced impairment of betaine-homocysteine methyltransferase (BHTM) activity or from components of lean body mass (LBM) submitted to any inflammatory disorder. LBM comprises a composite agglomeration of extrarenal tissues characterized by naturally occurring BHTM inactivity. As a result of cellular injury, LBM releases high concentrations of Hcy into the extracellular space, contrasting with the disruption of normal remethylation pathways. Hyperhomocysteinemia acts as a biomarker, reflecting the severity of insult and operating as an alarm signal. Elevated Hcy levels constitute a precursor pool recognized by a CBS coding region that reacts to meet increased methionine requirements in LBM tissues, using its enhanced production in hepatocytes. Preservation of methionine homeostasis benefits from its high metabolic priority and survival value.

Highlights

Human body composition studies indicate that nitrogen (N) is a key component of all proteins found in body tissues [1]
Both African surveys [22,26] show that the preservation of Met homeostasis in protein-depleted states is promoted by the CBS-induced upstream accumulation of Hcy in biological fluids, which serves as a precursor pool that can be readily driven into RM processes [25]
Rat [35] strains submitted to Met-restricted regimens have confirmed that the the SAM moiety (TS) pathway is impaired at the end of the deprivation period with an upstream elevation of Hcy and substantial body weight (BW) loss of 38% and 44%, respectively. These data are reminiscent of balance studies performed on pig models, which showed that withdrawal of Met and Cys from otherwise normal diets causes the greatest lean body mass (LBM) depletion, nearly equal to that generated by protein-free diets [36]

Summary

Introduction

Human body composition studies indicate that nitrogen (N) is a key component of all proteins found in body tissues [1]. Protein synthesis requires the sequential arrangement of amino acid (AA). Twenty canonical AAs have been identified in human proteins, of which eight are indispensable amino acids (IAAs), implying their obligatory supply in customary diets. Cys can furnish part of the total SAA needs of mammals [2], thereby ensuring a sparing effect of at least half the dietary Met requirements [3]. The usually recommended dietary allowances for both SAAs are 13 to 16 mg kg−1 day−1 or approximately. The proportion of Met in mixed body proteins reaches a mean of 2%–3%. We have collected data showing that, in contrast to the seven other IAAs, Met benefits from unique homeostatic mechanisms with survival value under conditions of chronic protein deprivation or excessive N body losses [4]

Main Methionine Characteristics

Methionine in Protein-Depleted States

Methionine in Excessive LBM Losses

Salvage Mechanisms for Methionine Homeostasis

Findings

Conclusions