Highlight
– In a double-blind randomized trial (NCT04783207), 4 weeks of 1000 mg/day urolithin A (UA) during an altitude training camp reduced indirect markers of muscle damage (creatine kinase) and lowered ratings of perceived exertion after a 3000 m time trial compared with placebo.
– UA supplementation was associated with proteomic signatures consistent with upregulated mitochondrial and downregulated inflammatory pathways in skeletal muscle, and a medium effect on mitophagy markers, but no measurable change in mitochondrial respiratory function.
– No statistically significant between-group improvement in 3000 m performance or time × treatment interaction for VO2max was observed; within-group VO2max increased more in the UA group (5.4%) than placebo (3.6%), but this did not translate into superior race performance over 4 weeks in highly trained male athletes.
Background
Urolithin A (UA) is a gut microbial metabolite derived from dietary ellagitannins (found in pomegranate, walnuts, and some berries). Preclinical studies indicate UA induces mitophagy—selective autophagic removal of dysfunctional mitochondria—and improves muscle function in model organisms. Early human studies suggested UA is safe and can modulate biomarkers of mitochondrial health in older adults, with improvements in endurance or muscle function in some cohorts. These data raise the possibility that UA could act as an ergogenic aid or recovery agent in athletes by enhancing mitochondrial quality control and reducing exercise-induced inflammation and muscle damage.
Study design
This was a double-blind, parallel-group, placebo-controlled randomized trial (ClinicalTrials.gov NCT04783207) in highly trained competitive male distance runners (n = 42; mean age 27.2 ± 1.0 years; mean VO2max 66.4 ± 0.6 mL·kg-1·min-1). Participants were randomized to receive 1000 mg/day UA (n = 22) or placebo (n = 20) for 4 weeks while attending an altitude training camp (~1700–2200 m).
Primary physiological outcomes measured at baseline and after 4 weeks included body composition, hemoglobin mass, running economy, and maximal aerobic capacity (VO2max). During the camp, weekly downhill running bouts were used to induce muscle stress and monitor recovery; capillary blood sampling assessed C-reactive protein (CRP) and creatine kinase (CK). A subset completed a 3000 m track time trial (n = 11 per arm) to evaluate performance, while another subset underwent skeletal muscle biopsy before and after supplementation (n = 9 placebo, n = 11 UA) for proteomic analysis and mitochondrial function assessment.
Key findings
Clinical outcomes:
- 3000 m performance: Neither group showed a statistically significant improvement in 3000 m time trial performance from baseline to 4 weeks (UA p = 0.116; placebo p = 0.771). There was no significant time × treatment interaction favoring UA.
- Perceived exertion: UA significantly lowered ratings of perceived exertion (RPE) during the 3000 m time trial compared with placebo (p = 0.02), indicating a subjective reduction in effort for similar external work.
- VO2max: Although the interaction test (time × treatment) for aerobic capacity was not statistically significant (p = 0.138), the UA group displayed a large within-group increase in VO2max (5.4%: 66.4 ± 0.8 to 70.0 ± 1.0 mL·kg-1·min-1; p = 0.009; Cohen’s d = -0.83). The placebo group had a smaller, non-significant within-group increase (3.6%: 66.4 ± 0.9 to 68.7 ± 1.0 mL·kg-1·min-1; p = 0.098; d = -0.54).
- Inflammation and muscle damage: UA supplementation markedly reduced indirect markers of muscle damage measured as total area under the curve for CK following the 3000 m time trial compared with placebo (CK AUC p < 0.0001). Effects on CRP were reported as part of inflammatory assessments, with proteomic data supporting downregulation of inflammatory pathways.
Skeletal muscle biology:
- Proteomics: Muscle biopsy proteomic screening revealed upregulation of pathways associated with mitochondrial function and downregulation of inflammatory pathways in the UA group compared with placebo.
- Mitophagy and mitochondrial function: UA produced a medium effect size for increased markers of mitophagy (d = -0.74) though this did not reach statistical significance. Measures of mitochondrial respiratory function showed no detectable change over 4 weeks.
Safety: The report does not describe serious adverse events attributable to UA. Prior human studies have indicated UA is generally well tolerated at studied doses.
Interpretation and clinical perspective
The trial provides clinically relevant insights for athletes and clinicians interested in nutritional strategies to improve recovery and training adaptation. The most robust findings relate to recovery physiology: UA reduced biochemical markers of exercise-induced muscle damage (CK) and altered the skeletal muscle proteome toward increased mitochondrial pathway signatures and decreased inflammatory pathways. These changes dovetail with the observed lower RPE during maximal effort running, suggesting UA may modify the subjective and biochemical response to acute high-intensity work.
However, these physiological and subjective improvements did not translate into statistically superior 3000 m performance in this cohort over a 4-week training period in an altitude camp. Important considerations include:
- Ceiling effects in highly trained athletes: Elite endurance athletes have limited room for short-term performance gains. A 4-week intervention may be insufficient to produce measurable race improvements beyond rigorous altitude training.
- Sample size and power: Subgroup sample sizes for performance (n = 11 per arm) and biopsy (n = 9–11 per arm) were small, limiting power to detect moderate between-group differences in performance or mitochondrial endpoints.
- Complex training environment: The intervention occurred during an altitude training camp, a potent stimulus for physiological adaptation (hematological and muscular). This could mask subtle supplementation effects or interact with UA mechanisms.
- Outcome discordance: The disconnect between proteomic/mitophagy signals and measures of mitochondrial respiratory function suggests early remodeling of mitochondrial quality control without immediate detectable changes in bulk mitochondrial respiration, or that available assays lacked sensitivity to capture functional improvement at this timescale.
Mechanistic plausibility
Preclinical data show UA activates mitophagy and improves muscle function in model systems. Human studies in older adults reported improved biomarkers of mitochondrial health and functional gains with UA supplementation. The current trial’s proteomic data align with these mechanisms—upregulation of mitochondrial pathways and downregulation of inflammatory signaling are biologically plausible mediators of improved recovery after muscle stress. Reduced CK and RPE provide functional correlates of this biology, but the lack of improved mitochondrial respiration suggests either a temporal lag between molecular remodeling and functional mitochondrial changes or that improvements occur in subpopulations of mitochondria not captured by whole-tissue assays.
Limitations
- Short duration (4 weeks) and relatively high athletic baseline limit generalizability to recreational athletes or longer training periods.
- Male-only cohort; results may not translate to female athletes, who can differ in mitochondrial biology and inflammatory responses.
- No measurement of plasma UA concentrations or stratification by gut microbial capacity to produce UA—important because endogenous UA production varies across individuals and may affect response to supplementation.
- Small sample sizes for performance and biopsy endpoints reduce precision and risk type II error for some comparisons.
Implications for practice
For clinicians advising athletes, the trial suggests UA supplementation at 1000 mg/day for 4 weeks is associated with improved recovery markers (lower CK) and lower perceived exertion after intense runs, supported by muscle proteomic shifts. However, there is insufficient evidence to recommend UA as a guaranteed ergogenic aid to improve short-term race performance in highly trained male distance runners. UA may be more applicable as a recovery adjunct or as an intervention in less-trained or older populations where prior studies have shown clearer effects.
Recommendations for future research
Future trials should address remaining uncertainties:
- Longer-duration interventions with larger sample sizes to determine whether proteomic changes translate into measurable mitochondrial function and performance gains.
- Inclusion of female athletes and a broader range of training statuses to assess generalizability.
- Measurement of plasma UA levels, pharmacokinetics, and microbiome profiles to identify responders versus non-responders and to explore dose–response relationships.
- Mechanistic studies combining high-resolution mitochondrial phenotyping (e.g., single-fiber respirometry), mitophagy flux assays, and longitudinal functional testing.
Conclusion
This randomized trial in highly trained male distance runners shows that 4 weeks of 1000 mg/day urolithin A during an altitude training block reduces biochemical markers of muscle damage and perceived exertion and induces proteomic changes consistent with enhanced mitochondrial pathways and reduced inflammation. Despite these recovery-related signals and a within-group increase in VO2max in the UA arm, UA did not produce statistically significant improvements in 3000 m performance when compared with placebo over the study period. UA appears promising as a recovery-modulating supplement, but evidence that it reliably improves short-term competitive performance in elite athletes is lacking. Larger, longer, and mechanistically focused trials are needed to define populations and contexts in which UA supplementation has meaningful performance or health benefits.
Funding and clinicaltrials.gov
ClinicalTrials.gov identifier: NCT04783207. Funding information was not specified in the trial abstract provided.
References
Whitfield J, McKay AKA, Tee N, McCormick R, Morabito A, Karagounis LG, Fouassier AM, D’Amico D, Singh A, Burke LM, Hawley JA. Evaluating the Impact of Urolithin A Supplementation on Running Performance, Recovery, and Mitochondrial Biomarkers in Highly Trained Male Distance Runners. Sports Med. 2025 Aug 21. doi: 10.1007/s40279-025-02292-5. Epub ahead of print. PMID: 40839339.
Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix A-A, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22(8):879–888.
Andreux PA, Blanco-Bose WE, Ryu D, Burdet F, Ibberson M, Aebischer P, et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019;1(6):595–603.
