Dysregulated Handling of Dietary Protein and Muscle Protein Synthesis After Mixed-Meal Ingestion in Maintenance Hemodialysis Patients

Abstract

Introduction: Skeletal muscle loss is common in patients with renal failure who receive maintenance hemodialysis (MHD) therapy. Regular ingestion of protein-rich meals are recommended to help offset muscle protein loss in MHD patients, but little is known about the anabolic potential of this strategy.

Methods: Eight MHD patients (age: 56 ± 5 years; body mass index [BMI]: 32 ± 2 kg/m²) and 8 nonuremic control subjects (age: 50 ± 2 years: BMI: 31 ± 1 kg/m²) received primed continuous L-[ring-²H₅]phenylalanine and L-[1-¹³C]leucine infusions with blood and muscle biopsy sampling on a nondialysis day. Participants consumed a mixed meal (546 kcal; 20-g protein, 59-g carbohydrates, 26-g fat) with protein provided as L-[5,5,5-²H₃]leucine-labeled eggs.

Results: Circulating dietary amino acid availability was reduced in MHD patients (41 ± 5%) versus control subjects (61 ± 4%; P = 0.03). Basal muscle caspase-3 protein content was elevated (P = 0.03) and large neutral amino acid transporter 1 (LAT1) protein content was reduced (P = 0.02) in MHD patients versus control subjects. Basal muscle protein synthesis (MPS) was ∼2-fold higher in MHD patients (0.030 ± 0.005%/h) versus control subjects (0.014 ± 0.003%/h) (P = 0.01). Meal ingestion failed to increase MPS in MHD patients (absolute change from basal: 0.0003 ± 0.007%/h), but stimulated MPS in control subjects (0.009 ± 0.002%/h; P = 0.004).

Conclusions: MHD patients demonstrated muscle anabolic resistance to meal ingestion. This blunted postprandial MPS response in MHD patients might be related to high basal MPS, which results in a stimulatory ceiling effect and/or reduced plasma dietary amino acid availability after mixed-meal ingestion.

Keywords: chronic kidney disease; inflammation; insulin resistance; nutrition; protein digestion.

Figure 1

Plasma leucine (in micromoles per liter) (a), blood glucose (in milligram per deciliter) (b), and plasma insulin concentrations (in micro−International Units per milliliter) (c) in the basal state and after mixed-meal ingestion in maintenance hemodialysis (MHD) patients (n = 8) and control subjects (n = 8). Insets show the areas under the time curves (AUC) for the fed state. Dashed lines refer to meal ingestion. Data are mean ± SEMs. *Significantly different compared with MHD at that time point. Insets: all P > 0.05.

Figure 2

Plasma L-[5,5,5-²H₃]leucine (a), L-[1-¹³C]leucine (b), α-[¹³C]-ketoisocaproate (c), and L-[ring-²H₅]phenylalanine (d) enrichments over time in the basal state and after meal consumption in maintenance hemodialysis (MHD) patients (n = 8) and control subjects (n = 8). Dashed lines refer to meal ingestion. Data are expressed as mole percent excess (MPE) (a,b,d) and atom percent excess (APE) (c). Data are mean ± SEMs. *Significantly different compared with MHD at that time point.

Figure 3

Exogenous leucine rate of appearance (R_a), index of protein digestion and absorption kinetics (in nanomole leucine/kg per min) (a), and the amount of dietary protein−derived amino acids that appeared in circulation (percentage dietary leucine that appeared in the plasma after meal consumption) (b) after mixed-meal ingestion in maintenance hemodialysis (MHD) patients (n = 8) and control subjects (n = 8). Dashed line refers to mixed-meal ingestion. Gray shapes denote individual data in each group. Data are mean ± SEMs. *Significantly different compared with MHD at that time point.

Figure 4

Endogenous leucine rate of appearance (R_a) (a), total leucine R_a (b), and total leucine R_d (c) over time in the basal state and after meal consumption in maintenance hemodialysis (MHD) patients (n = 8) and control subjects (n = 8). Dashed lines refer to meal ingestion. Data are mean ± SEMs.

Figure 5

Whole-body leucine metabolism shown as the area under the curve of endogenous rate of appearance (marker of protein breakdown), nonoxidative leucine disposal (marker of protein synthesis), leucine oxidation (oxidation), and net leucine balance in the basal state and after meal consumption in maintenance hemodialysis (MHD) patients (n = 8) and control subjects (n = 8). Dashed line refers to meal ingestion. Data are mean ± SEMs.

Figure 6

Muscle protein content of large neutral amino acid transporter (LAT1) (a) and phosphorylation of mammalian target of rapamycin complex 1 (mTORC1) at Ser2448 (b) before and after mixed-meal ingestion in maintenance hemodialysis (MHD) patients (n = 8) and control subjects (n = 8). Data are mean ± SEMs. AU, arbitrary units. *Significantly different compared with MHD at that time point.

Figure 7

Muscle protein content for caspase-3 (a) and ubiquitin (b) before and after mixed-meal ingestion in maintenance hemodialysis (MHD) patients (n = 8) and control subjects (n = 8). Data are mean ± SEMs. AU, arbitrary units. *Significantly different compared with MHD at that time point.

Figure 8

Myofibrillar protein synthesis (a) expressed as the fractional synthesis rate (FSR) before (basal) and after mixed meal ingestion in MHD patients (n = 8) and control subjects (n = 8). Individual data for the myofibrillar protein synthesis responses in MHD patients and control subjects (b). *Significantly different compared with MHD at that time point. Note different scales on y-axes between graphs. †Significantly different from basal.