5.1. Mitochondrial Cytopathy
There have been a number of small case series and case reports on the effects of creatine supplementation in mitochondrial cytopathies. A case report of an 18 year old with MELAS syndrome taking creatine at 12 g/d for 12 days followed by 5g/d for 28 months showed a definite improvement in MRI and MR spectroscopy values with an increase in brain creatine as well as marked behavior and cognitive improvements. There appeared to be a deterioration of renal function with an impairment of renal creatinine clearance in this patient who had pre-existing nephropathy (Barisic et al., 2002). A small open study in four patients with mitochondrial cytopathy (Kearns Sayre syndrome, NARP and MELAS) evaluated the effects of CrM supplementation (0.1-0.35g/kg/day) (Komura et al., 2003). This was actually a retrospective study for nine months to almost five years and found an improvement in cycle ergometry performance of about 12% during steady-state exercise with no significant effects on peak power
(Komura et al., 2003). A similar study in four patients (Kearns Sayre syndrome, NARP and MELAS) evaluated the efficacy of CrM (0.1-0.2 g/kg/day for three months) on cycle ergometry performance (Borchert et al., 1999). There was an increase in maximal power ranging from 8 to 17% with an increase in endurance performance ranging from 30 to 57%. The latter two studies, with a total of 9 patients, demonstrated improvements in cycle ergometry performance.
Our group used a randomized double-blind cross-over design in 7 patients with MELAS syndrome randomized to CrM (10g/day for 2wk ^ 3 g/d for 1 wk) and a placebo (3wk) with a five week wash-out period (Tarnopolsky et al., 1997). We found improvements in high-intensity repetitive grip strength and dorsi-flexion strength during a two-minute performance trial with no improvement in VO2 max in a cycle ergometry test, and no statistically significant improvements in body composition (Tarnopolsky et al., 1997). Subsequent to this study, there were two randomized double-blind trials in patients with mitochondrial DNA deletions (predominantly CPEO) with a few patients with Kearns Sayre syndrome (Klopstock et al., 2000; Kornblum et al., 2005). One study evaluated the efficacy of CrM supplementation (20 g/d) in 16 patients with CPEO or isolated mitochondrial myopathy using a four-week randomized, double-blind, cross-over design. There were small trends towards an improvement in MRC score (P = 0.14) and non-ischemic isokinetic biceps flexion strength (P = 0.16); yet neuromuscular symptoms and Hammer-Smith score, functional tasks, ataxia and peak biceps strength were not different. The authors' conclusions were that the power of the study was limited and that in the future, larger multi-center trials are needed (Klopstock et al., 2000). A subsequent study in patients with CPEO and Kearns Sayre syndrome evaluated the efficacy of CrM (150 mg/kg/d) or placebo using a cross-over design (Kornblum et al., 2005). 31P-MRS did not show any improvement with supplementation nor was there an enhancement in post-exercise PCr recovery (an indicator of mitochondrial function). There were no significant differences measured between the treatment arms; however, some of the outcomes such as the maximal voluntary contraction strength after aerobic exercise showed some trends towards an improvement on creatine (P = 0.14). The authors' conclusion was that the short study duration and limited number of patients may have led to a type 2 error (Kornblum et al., 2005). Finally, our group has recently published the results of a randomized, double-blind trial showing that a combination of CrM + coenzyme Q10 + a-lipoic acid resulted in lower lactate and 8-isoprostanes (a marker of oxidative stress) and higher fat-free mass (only in the MELAS sub-group) as compared with a placebo (Rodriguez et al., 2007). An issue with the latter study is that it was not possible to determine what proportion of the effects observed were due to the CrM component. Overall, the data with respect to the use of CrM supplementation in mitochondrial cytopathy is equivocal in spite of the strong theoretical evidence for benefit. Findings similar to those seen in young healthy individuals (e.g., an increase in repetitive high intensity activity) (Casey et al., 1996; Mihic et al., 2000) have been reported in these patients; however, whether this translates into functional improvement and long-term benefit remains to be seen. With a disease such as MELAS that has huge variability in clinical signs and symptoms (Tarnopolsky and Raha, 2005), the ability to detect differences in functional outcomes will be difficult and clearly will require large multi-center trials.
Given the increased reliance on alternative anaerobic energy pathways in response to severely attenuated glycogenolysis seen in McArdle's disease, it would appear to be an ideal candidate for a disease that should respond to CrM supplementation. One study evaluated 9 patients with McArdle's disease randomized to CrM (150mg/kg/d for one week, followed by 60mg/kg/d for 4wk) versus placebo with a five-week washout period in between (Vorgerd et al., 2000). There was a non-significant increase in muscle PCr content (P = 0.15) with no enhancement in PCr recovery following either aerobic or ischemic exercise. During ischemic exercise, the force-time integral (P = 0.03), PCr depletion and Pi accumulation (P = 0.05) were higher on creatine (Vorgerd et al., 2000). During aerobic exercise there was a significant increase in PCr depletion (P = 0.006), and surface electromyography improved with respect to the mean frequency in the creatine group. There was no evidence of serological or clinical side effects during the trial (Vorgerd et al., 2000). This same group completed a larger trial with 19 patients with McArdle's disease patients, using a similar design but a constant higher dose of CrM (150mg/kg/d for 5wk) (Vorgerd et al., 2002). Interestingly, there was a worsening of muscle pain limitations in daily activity and negative affects on the surface EMG values for the creatine group (Vorgerd et al., 2002). The overall conclusion from both studies was that high-dose creatine administration has a negative effect on function yet a dose of around 60 mg/kg/d appears to confer benefit with respect to muscle function. It may be that a limited ability to load muscle with creatine in these patients may play some role (Vorgerd et al., 2002); however, that would not explain the worsening of symptoms with the higher dose. It is likely that some of the failure for creatine to be of clinical benefit in these patients is due to the inability of McArdle's disease patients to acidify muscle, and hence the flux in the direction of ATP generation by the PCr/Cr pathway would be inhibited. Currently, it is unclear why patients with McArdle's disease show an opposite response to different CrM doses, but more work is needed in this area.
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