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

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.

Keywords: cystathionine-β-synthase; homocysteine; inflammatory disorders; lean body mass; methionine pool size; protein malnutrition; sarcopenia; transthyretin.

Figure 1

Main endogenous pathways of methionine metabolism. Compounds: ATP, adenosyl-triphosphate; Cys, cysteine; Cysta, cystathionine; GSH, glutathione; H₂S, hydrogen sulfide; 3MP, 3-mercaptopyruvate; SAH, S-adenosyl-homocysteine; SAM, S-adenosyl-methionine; Tau, taurine; THF, tetrahydrofolate; SO₄^2-, sulfate oxyanions. Enzymes: (1) Met adenosyl-transferase; (2) CompoundsSAM methyltransferase; (3) adenosyl-homocysteinase; (4) BHMT, betaine-homocysteine-methyltransferase; (5) MS; methionine-synthase; (6) CBS, cystathionine β-synthase; (7) CGL, cystathionine γ-lyase; (8) γ-glutamyl-synthase; (9) γ-glutamyl-transpeptidase (adapted from [4]).

Figure 2

Evolutionary patterns of lean body mass (LBM) values throughout the human lifespan. Compilation of seven different clinical investigations performed in healthy subjects from birth to very old age and showing body accretion of total body potassium (TBK) values determined by the measurement of the naturally occurring radioisotope ⁴⁰K using dual-energy X-ray absorptiometry (DXA). The results are plotted against age on double-logarithmic coordinates. Ninety-five percent (95%) of TBK is sequestered within metabolically active tissues and narrowly correlated with total body N (TBN), making this last parameter a valuable tool to appraise LBM values in health and disease (Forbes, [1]). Figure 2 shows that normal TBK concentrations are approximately 140–160 g in adult men and 90–110 g in adult women, yielding male/female K and N ratios of approximately 1.4:1.

Figure 3

Evolutionary profiles of transthyretin (TTR) concentrations throughout the human lifespan. Evolutionary profiles of TTR concentrations measured in the blood samples from 67,720 healthy U.S. citizens using immunoturbidimetric analysis (Bienvenu et al., [40]). TTR and LBM values manifest closely superimposable trajectories. The figure shows the lowest values measured at birth, linear progression without sexual difference until the onset of puberty, occurrence of sexual dimorphism with more pronounced rise in adult males because of a larger musculature, followed by plateau levels until the age of 60 years, and finally gradual downsizing toward sarcopenia in both sexes, with a steeper slope observed in elderly males. Both TTR and LBM curves show comparable abrupt S-shape elevations from the onset of adolescence until the beginning of adulthood, which are partially obliterated due to changes in the graduation of the abscissa scales.