Melatonin protects against uric acid-induced mitochondrial dysfunction, oxidative stress, and triglyceride accumulation in C₂C₁₂myotubes

Abstract

Excess uric acid has been shown to induce oxidative stress, triglyceride accumulation, and mitochondrial dysfunction in the liver and is an independent predictor of type-2 diabetes. Skeletal muscle plays a dominant role in type 2 diabetes and presents a large surface area to plasma uric acid. However, the effects of uric acid on skeletal muscle are underinvestigated. Our aim was therefore to characterize the effects of excessive uric acid on oxidative stress, triglyceride content, and mitochondrial function in skeletal muscle CC myotubes and assess how these are modulated by the antioxidant molecule melatonin. Differentiated CC myotubes were exposed to 750 µM uric acid or uric acid + 10 nM melatonin for 72 h. Compared with control, uric acid increased triglyceride content by ~237%, oxidative stress by 32%, and antioxidant capacity by 135%. Uric acid also reduced endogenous ROUTINE respiration, complex II-linked oxidative phosphorylation, and electron transfer system capacities. Melatonin counteracted the effects of uric acid without further altering antioxidant capacity. Our data demonstrate that excess uric acid has adverse effects on skeletal muscle similar to those previously reported in hepatocytes and suggest that melatonin at a low physiological concentration of 10 nM may be a possible therapy against some adverse effects of excess uric acid. Few studies have investigated the effects of uric acid on skeletal muscle. This study shows that hyperuricemia induces mitochondrial dysfunction and triglyceride accumulation in skeletal muscle. The findings may explain why hyperuricemia is an independent predictor of diabetes.

The Association between Serum Uric Acid and Appendicular Skeletal Muscle Mass and the Effect of Their Interaction on Mortality in Patients on Peritoneal Dialysis

“…The beneficial effects of UA as an antioxidant in bone health have been shown [41,42], but there are few studies addressing the direct effects of UA on muscle health. Recently, an in vitro study found that exogenous UA increased oxidative stress in C2C12 skeletal muscle cells [43]. Therefore, the exact mechanism underlying the positive association between SUA and ASMI remains unclear, and additional studies are required.…”

Urine metabolic profiles in paediatric asthma

“…Similar findings were reported in animal and human studies, showing decreased serum uric acid levels in asthma patients according to disease severity . The relationship between uric acid, the final product of purine metabolism, inflammation and oxidative stress remains controversial, with studies showing high uric acid concentrations inducing inflammation and oxidative stress, resulting in apoptosis . However, increasing studies showed uric acid as a candidate asthma‐specific biomarker based on its antioxidative roles in decreasing ROS and preventing oxidative damage .…”

The influence of dietary interventions on paraclinical parameters in patients with metabolic syndrome

“…Uric acid has been found to be strongly associated with triglycerides, regardless of age, sex, smoking, alcohol consumption, obesity and insulin resistance, in a study published in China 26 . Uric acid and triglyceride levels have also been linked to oxidative stress and mitochondrial dysfunction 27 , but there was also a decrease in the level of uric acid and triglycerides following the administration of glycine and tryptophan without diet therapy [28][29][30] .…”