No effect of triheptanoin on exercise performance in McArdle disease

Abstract

Objective: To study if treatment with triheptanoin, a 7-carbon triglyceride, improves exercise tolerance in patients with McArdle disease. McArdle patients have a complete block in glycogenolysis and glycogen-dependent expansion of tricarboxylic acid cycle (TCA), which may restrict fat oxidation. We hypothesized that triheptanoin metabolism generates substrates for the TCA, which potentially boosts fat oxidation and improves exercise tolerance in McArdle disease.

Methods: Double-blind, placebo-controlled, crossover study in patients with McArdle disease completing two treatment periods of 14 days each with a triheptanoin or placebo diet (1 g/kg/day). Primary outcome was change in mean heart rate during 20 min submaximal exercise on a cycle ergometer. Secondary outcomes were change in peak workload and oxygen uptake along with changes in blood metabolites and respiratory quotients.

Results: Nineteen of 22 patients completed the trial. Malate levels rose on triheptanoin treatment versus placebo (8.0 ± SD2.3 vs. 5.5 ± SD1.8 µmol/L, P < 0.001), but dropped from rest to exercise (P < 0.001). There was no difference in exercise heart rates between triheptanoin (120 ± SD16 bpm) and placebo (121 ± SD16 bpm) treatments. Compared with placebo, triheptanoin did not change the submaximal respiratory quotient (0.82 ± SD0.05 vs. 0.84 ± SD0.03), peak workload (105 ± SD38 vs. 102 ± SD31 Watts), or peak oxygen uptake (1938 ± SD499 vs. 1977 ± SD380 mL/min).

Interpretation: Despite increased resting plasma malate with triheptanoin, the increase was insufficient to generate a normal TCA turnover during exercise and the treatment has no effect on exercise capacity or oxidative metabolism in patients with McArdle disease.

Figure 1

The suggested principles of treatment with triheptanoin in McArdle disease. The pyruvate pool is depleted in patients with McArdle disease due to the block in glycogenolysis. This may reduce levels of oxaloacetate in the tricarboxylic acid cycle (TCA), which slows the turnover rate of the TCA and limits the entry of acetyl‐CoA to the TCA. Almost all naturally occurring fatty acids have an even number of carbons. They are metabolized through beta‐oxidation cleaving off two carbons at a time producing acetyl‐CoA. Triheptanoin is a triglyceride of three 7‐carbon fatty acids (C7). The final step in the metabolism of odd number carbon fatty acids, such as C7, produces both acetyl‐CoA and propionyl‐CoA, which are converted to succinyl‐CoA, an intermediate of the TCA. The supplied succinyl‐CoA can potentially replenish the pool of TCA intermediates, boost the turnover of the TCA and enhance oxidative phosphorylation through increased metabolism of fatty acids and other substrates passing through the cycle. The liver can convert C7 to 5‐carbon (C5) ketone bodies, which are readily exported from the liver to the muscle. The breakdown of C5‐ketone bodies in the muscle produces acetyl‐CoA and propionyl‐CoA and contributes to the delivery of intermediates to the TCA.

Figure 2

Study design of the randomized double‐blind crossover study comparing triheptanoin to placebo treatment in McArdle disease. Participants completed two treatment periods of 14 days with triheptanoin and placebo in a random sequence (Seq. 1 or Seq. 2) separated by a ≥ 1‐week washout period, and assessments with cycle ergometry exercise were performed on a screening visit and at 4 study visits.

Figure 3

Participant enrollment, allocation, and completion in a randomized double‐blind crossover study where the included participants with McArdle disease were allocated 1:1 to two 14‐days periods of treatment with triheptanoin and placebo in a random sequence separated by a >1‐week washout period.

Figure 4

Heart rate and self‐reported exertion during submaximal (until 20 min) to peak exercise in 19 McArdle patients at baseline and after treatment with triheptanoin and placebo for 14 days in a double‐blind crossover study. Values are means with error bars of standard deviations.

Figure 5

Individual and mean changes from placebo to active treatment and from baseline to active treatment in (A) submaximal exercise heart rate, (B) submaximal exercise respiratory quotient (RQ), (C) peak exercise workload and (D) peak oxygen uptake in 19 patients with McArdle disease in a double‐blind crossover study investigating the effect of 14 days treatment with triheptanoin.

Figure 6

Plasma metabolite concentrations during submaximal (20 min) to peak exercise in 19 McArdle patients at baseline and after treatment with triheptanoin and with placebo for each 14 days in a double‐blind crossover study. *P < 0.001 versus placebo and baseline. Values are means with error bars of standard deviations.