Increased skeletal muscle amino acid release with light exercise in deconditioned patients with heart failure

To the Editor:

The existence of muscle metabolic alterations in patients with chronic heart failure (CHF) (1) led us to test the hypothesis that even a light exercise mimicking a daily life activity (2) in CHF may induce an excess of muscle amino acid release. We focused in particular on phenylalanine (Phe) release because this amino acid is neither synthesized nor degraded within muscle (3).

Twenty untrained, clinically stable, normonourished fasting male patients (Table 1)with moderate to severe CHF at morning underwent hemodynamic procedures to measure femoral blood flow, arterial and venous amino acid concentrations (branched chain amino acids [BCAAs: valine, leucine, isoleucine], histidine, alanine, glutamic acid, glutamine, and taurine), as well as pH and lactate and free fatty acid (FFA) levels both at baseline and at 20 W bicycle exercise oxygen consumption (Vo₂, ml·kg⁻¹·min⁻¹) steady state.

The net uptake and/or release of muscle amino acids was calculated as: Net balance = ([A] − [V]) × Fwhere A− Vis the femoral arteriovenous difference in amino acid concentrations and Fis leg blood flow. Thus, a net muscle uptake means amino acid utilization, whereas a net muscle release indicates increased protein breakdown and/or amino acid alteration.

At rest, controls and CHF had similar arterial amino acid concentrations (unpaired ttest). Net muscle uptake and/or release of amino acids by controls and CHF, at rest and during exercise, are illustrated in Figure 1.At rest, CHF took up all amino acids except taurine, which was released, whereas controls released amino acids with the exception of glutamic acid and taurine, which were taken up. During exercise, CHF, but not controls, released significant amounts of Phe (from 38.2 ± 2.4 to −42.3 ± 3.2 μmol·l⁻¹·min⁻¹; p < 0.01), the three BCAAs; histidine, alanine (p < 0.05 in all cases), and glutamine (p < 0.01). The uptake of glutamic acid declined (p < 0.01) and taurine was taken up (p < 0.01), resulting in levels higher than in controls (p < 0.05) (paired ttest).

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Figure 1

Muscle amino acid net uptake and/or release (μmol·l⁻¹·min⁻¹) at rest and during light exercise (20 W) in controls (open bars)and chronic heart failure (CHF) patients (solid bars).

At rest, arterial FFA concentration as well as FFA release was higher in CHF than in controls (p < 0.05 and <0.001, respectively). During exercise the difference in FFA release between CHF and controls declined but remained significant (p < 0.01). At rest, blood femoral vein was acidotic in CHF (pH = 7.34 ± 0.02 vs. 7.41 ± 0.01 in controls; p < 0.05); during the effort, the pH of CHF further decreased (7.31 ± 0.01; p < 0.01).

This investigation shows that patients with CHF exercising at a light workload have a net muscle release of both Phe and other amino acids. The mechanisms responsible for the net release of Phe during exercise in CHF patients may include alterations in intermediary and energy metabolism within muscle cells, intracellular acidosis, and cytokine production. Indeed, the low intramuscular glycogen concentration in resting CHF patients (4) may make muscle energy metabolism more dependent on alternative substrates such as amino acids derived from cellular-free pool and/or accelerate protein degradation. Carbohydrate depletion, in fact, favors muscle protein breakdown, whereas carbohydrate loading significantly restricts protein degradation (5). Furthermore, the documented glycolytic and oxidative pathway alterations in CHF (4) could contribute to increasing muscle protein utilization and amino acid oxidation.

The muscle metabolic acidosis can worsen the net negative balance of Phe in CHF; this is because low pH acts as a catabolic stimulus in normal adults (6). Notably, the acidosis in our CHF patients may be enhanced by the net loss of muscle histidine, the main intracellular buffer in the muscle. A possible cytokine overproduction in exercising CHF may also contribute to release of Phe from muscles (7). The release of BCAAs confirms the existence of abnormal amino acid metabolism in exercising CHF because exercise normally causes muscle to extract BCAAs from the plasma and not to release them into the bloodstream (8).

The finding of a positive net balance of muscle amino acids (with the exception of glutamic acid), particularly of alanine, in resting overnight fasting CHF is the opposite of what occurred in controls, insulin activity being normally low after overnight fasting. It is likely that a normal availability of arterial amino acids in CHF patients, together with increased serum catecholamine levels, may have counteracted muscle release of amino acids in the fasting state (9,10). During exercise, CHF patients release alanine, as do normal subjects at rest.

The persistence of muscle glutamic acid uptake, the increased glutamine release, and the increased taurine uptake may all indicate an increased muscle utilization of these amino acids by CHF during exercise (11,12). The release of FFA may suggest that, in CHF, an increased muscle lipolysis also occurred (13).

In brief, the study shows that, during light exercise, untrained patients with CHF release a number of muscle amino acids, suggesting a possible abnormal muscle amino acid metabolism. Based on these data and on Phe release (3) we hypothesize an occurrence of muscle protein overdegradation in deconditioned exercising CHF. If so, it is conceivable that repeated daily-life physical activities by untrained CHF patients may contribute to a negative nitrogen balance (14) and to muscular wasting.

Finally, in this context appropriate physical training can counteract muscle amino acid release and protein degradation in untrained CHF (15).

• American College of Cardiology Foundation