Effect of allopurinol on phosphocreatine recovery and muscle function in older people with impaired physical function: a randomised controlled trial

Abstract

Background Allopurinol has vascular antioxidant effects and participates in purinergic signalling within muscle. We tested whether allopurinol could improve skeletal muscle energetics and physical function in older people with impaired physical performance. Methods We conducted a randomised, double blind, parallel group, placebo-controlled trial, comparing 20 weeks of allopurinol 600 mg once daily versus placebo. We recruited community-dwelling participants aged 65 and over with baseline 6-min walk distance of <400 m and no contraindications to magnetic resonance imaging scanning. Outcomes were measured at baseline and 20 weeks. The primary outcome was post-exercise phosphocreatine (PCr) recovery rate measured using 31P magnetic resonance spectroscopy of the calf. Secondary outcomes included 6-min walk distance, short physical performance battery (SPPB), lean body mass measured by bioimpedance, endothelial function and quality of life. Results In total, 124 participants were randomised, mean age 80 (SD 6) years. A total of 59 (48%) were female, baseline 6-min walk distance was 293 m (SD 80 m) and baseline SPPB was 8.5 (SD 2.0). Allopurinol did not significantly improve PCr recovery rate (treatment effect 0.10 units [95% CI, −0.07 to 0.27], P = 0.25). No significant changes were seen in endothelial function, quality of life, lean body mass or SPPB. Allopurinol improved 6-min walk distance (treatment effect 25 m [95% 4–46, P = 0.02]). This was more pronounced in those with high baseline oxidative stress and urate. Conclusion Allopurinol improved 6-min walk distance but not PCr recovery rate in older people with impaired physical function. Antioxidant strategies to improve muscle function for older people may need to be targeted at subgroups with high baseline oxidative stress.

The association of allopurinol with persistent physical disability and frailty in a large community based older cohort

“…The strong protective association between allopurinol use and physical disability may be explained by allopurinol conferring benefits on improving gout symptoms and multiple gout‐associated complications, on physical functioning, including gout‐associated arthritic pain and stiffness, and cardiometabolic outcomes. In supporting our findings, a small‐scale randomized trial found that allopurinol improved 6‐min walk distance in 214 patients with impaired physical function (6‐min walk distance <400 m), though it did not improve muscle efficiency as measured by post‐exercise skeletal muscle phosphocreatine recovery rate 31 . A more recent cross‐sectional study including 296 patients who had undergone hemodialysis found that use of a xanthine oxidoreductase inhibitor (allopurinol, febuxostat, or topiroxostat) was associated with reduced risks of sarcopenia and severe sarcopenia, greater muscle mass and strength, and a better physical performance 32 .…”

“…In supporting our findings, a small-scale randomized trial found that allopurinol improved 6-min walk distance in 214 patients with impaired physical function (6-min walk distance <400 m), though it did not improve muscle efficiency as measured by post-exercise skeletal muscle phosphocreatine recovery rate. 31 A more recent cross-sectional study including 296 patients who had undergone hemodialysis found that use of a xanthine oxidoreductase inhibitor (allopurinol, febuxostat, or topiroxostat) was associated with reduced risks of sarcopenia and severe sarcopenia, greater muscle mass and strength, and a better physical performance. 32 Our sensitivity analysis has shown a similar positive result of the association between allopurino and physical disability in the overall ASPREE population.…”

Association between mitochondrial function measured by 31P magnetic resonance spectroscopy and physical performance in older people with functional impairment

“…The analyses described in this paper used data from the ALFIE (Allopurinol for Functional Impairment) trial 13 . The trial enrolled 124 people aged 65 and over with impaired physical performance (6‐min walk distance <400 m) and randomized them to receive 600 mg allopurinol or matching placebo for 20 weeks.…”

“…Both sets of tests were conducted at baseline and at 20 weeks after the intervention. The full 31P MRS acquisition and analysis details have been published previously 13 . In brief, participants were scanned using a 3T Siemens MRI scanner (Trio/PrismaFit, Siemens Healthineers, Erlangen, Germany).…”

“…A dual‐tuned 1 H/ 31 P coil was used to acquire spectra every 4.2 s before exercise and during recovery starting immediately after cessation of plantarflexion exercise. Spectroscopy data were processed using JMRUI 15 to obtain a series of 31P MRS measures including phosphocreatine recovery rate, ATP, inorganic phosphate and total phosphocreatine levels pre‐and post‐exercise as previously described 13,16 . The maximal rate of PCr recovery was calculated from the maximum slope of the fitted graph for each recovery curve, with results presented both un‐normalized and normalized for PCr depletion.…”