Abstract:IMPORTANCEAging is associated with a decline in mitochondrial function and reduced exercise capacity. Urolithin A is a natural gut microbiome-derived food metabolite that has been shown to stimulate mitophagy and improve muscle function in older animals and to induce mitochondrial gene expression in older humans. OBJECTIVE To investigate whether oral administration of urolithin A improved the 6-minute walk distance, muscle endurance in hand and leg muscles, and biomarkers associated with mitochondrial and cell… Show more
“… 58 Previous data in elderly subjects showed that UA supplementation reduced plasma acylcarnitines. 28 , 29 The current study reproduced these data after long-term administration and in a different population, albeit only at the 500 mg UA dose. These data suggest that the impact of UA on acylcarnitines might be function of the length of intervention and dosing.…”
Section: Discussionsupporting
confidence: 74%
“… 33 Acylcarnitines were reduced in the UA 500 mg group and middle- to long-chain acylcarnitines were the most downregulated species ( Figure 3 B), as reported in previous clinical studies. 28 , 29 No changes occurred in the UA 1,000 mg cohort ( Figure 3 B), suggesting a possible time/duration effect of UA on this plasma biomarker. Figure 3 Effect of Urolithin A on systemic biomarkers of mitochondrial health and inflammation (A) Dose-dependent increase in plasma UA (left), UA-glucuronide (middle), and UA-sulfate (right) plasma levels comparing baseline with the last day of the 4-month treatment period for placebo, UA 500 mg, and UA 1,000 mg doses (n = 27, placebo and UA 500 mg; n = 25, UA 1,000 mg).…”
Section: Resultsmentioning
confidence: 94%
“…The new study builds on findings from previously reported trials with UA in older adults that demonstrated both the biological impact of UA on mitochondrial health in skeletal muscle 28 and an improvement in muscle endurance and resistance to fatigue with long-term UA supplementation. 29 The present trial was designed to assess the benefits of UA in middle-aged adults on a range of physiological and biomarker endpoints over a longer period of 4 months. Muscle biopsies have been used for a first comprehensive analysis of mRNA and protein biomarkers modulated in humans after long-term intervention with UA.…”
Section: Discussionmentioning
confidence: 99%
“… 28 A recent randomized clinical trial in older adults also demonstrated improvements in muscle endurance with long-term UA intake. 29 …”
“… 58 Previous data in elderly subjects showed that UA supplementation reduced plasma acylcarnitines. 28 , 29 The current study reproduced these data after long-term administration and in a different population, albeit only at the 500 mg UA dose. These data suggest that the impact of UA on acylcarnitines might be function of the length of intervention and dosing.…”
Section: Discussionsupporting
confidence: 74%
“… 33 Acylcarnitines were reduced in the UA 500 mg group and middle- to long-chain acylcarnitines were the most downregulated species ( Figure 3 B), as reported in previous clinical studies. 28 , 29 No changes occurred in the UA 1,000 mg cohort ( Figure 3 B), suggesting a possible time/duration effect of UA on this plasma biomarker. Figure 3 Effect of Urolithin A on systemic biomarkers of mitochondrial health and inflammation (A) Dose-dependent increase in plasma UA (left), UA-glucuronide (middle), and UA-sulfate (right) plasma levels comparing baseline with the last day of the 4-month treatment period for placebo, UA 500 mg, and UA 1,000 mg doses (n = 27, placebo and UA 500 mg; n = 25, UA 1,000 mg).…”
Section: Resultsmentioning
confidence: 94%
“…The new study builds on findings from previously reported trials with UA in older adults that demonstrated both the biological impact of UA on mitochondrial health in skeletal muscle 28 and an improvement in muscle endurance and resistance to fatigue with long-term UA supplementation. 29 The present trial was designed to assess the benefits of UA in middle-aged adults on a range of physiological and biomarker endpoints over a longer period of 4 months. Muscle biopsies have been used for a first comprehensive analysis of mRNA and protein biomarkers modulated in humans after long-term intervention with UA.…”
Section: Discussionmentioning
confidence: 99%
“… 28 A recent randomized clinical trial in older adults also demonstrated improvements in muscle endurance with long-term UA intake. 29 …”
“…To further evaluate the potential of mitochondrial bioenergetics and proteostasis modulation in the treatment of CS in the early stage of the disease we tested the efficacy UA alone or in combination with BZ in a previously described CS zebrafish model ( 45 ). The mitochondrial proteostasis modulator UA was recently characterized and showed no toxicity in a human clinical trial ( 85 – 87 ). We discovered that UA in combination with BZ synergistically increased the survival of CS embryos and significantly reduced the occurrence of developmental defects.…”
Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies.Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of Costello mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in the CS mice and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with Costello syndrome may benefit from treatment with mitochondrial modulators.
Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in inflammation and fibrosis that ultimately affect the overall muscle biomechanics. At the opposite end of the spectrum of muscle diseases, age‐related sarcopenia is a common condition that affects an increasing proportion of the elderly. Although characterized by different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. Here, the therapeutic effects of Cyclo Histidine‐Proline (CHP) against DMD and sarcopenia are evaluated. In the mdx mouse model of DMD, it is shown that CHP restored muscle contractility and force production, accompanied by the reduction of fibrosis and inflammation in skeletal muscle. CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age‐related sarcopenia. These findings from two different models of muscle dysfunction hence warrant further investigation into the effects of CHP on muscle pathologies in animal models and eventually in patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
