High throughput screening of mitochondrial bioenergetics in human differentiated myotubes identifies novel enhancers of muscle performance in aged mice

Abstract

Mitochondrial dysfunction is increasingly recognized as a contributor to age-related muscle loss and functional impairment. Therefore, we developed a high throughput screening strategy that enabled the identification of compounds boosting mitochondrial energy production in a human skeletal muscle cell model. Screening of 7949 pure natural products revealed 22 molecules that significantly increased oxygen consumption and ATP levels in myotubes. One of the most potent compounds was the flavanone hesperetin. Hesperetin (10 µM) increased intracellular ATP by 33% and mitochondrial spare capacity by 25%. Furthermore, the compound reduced oxidative stress in primary myotubes as well as muscle tissue in vivo. In aged mice administration of hesperetin (50 mg/kg/d) completely reverted the age-related decrease of muscle fiber size and improved running performance of treated animals. These results provide a novel screening platform for the discovery of drugs that can improve skeletal muscle function in patients suffering from sarcopenia or other disorders associated with mitochondrial dysfunction.

Undaria pinnatifidaextract feeding increases exercise endurance and skeletal muscle mass by promoting oxidative muscle remodeling in mice

“…Hesperetin increased p‐AMPK, PGC‐1α, ERRγ, and ERRα, SIRT1, and NRF2 expression, and caffeic acid also upregulated the protein expression of PGC‐1α and SIRT1, signaling molecules determined to be controlled by U pinnatifida extracts. Hesperetin was also reported to enhance muscle performance and mitochondria biogenesis by increasing PGC‐1α and NRF2 expression in previous study 70 . Caffeic acid promotes myogenic differentiation, as shown in our previous report 71 .…”

Hesperidin modulates dextran sulfate sodium‐induced ulcerative colitis in rats: Targeting sphingosine kinase‐1‐ sphingosine 1 phosphate signaling pathway, mitochondrial biogenesis, inflammation, and apoptosis

“…PGC1‐α was decreased in the UC group, which may be due to its high acetylation by sirtuin 1 within the intestinal epithelium as well as an increase in its protein degradation by ubiquitination after DSS exposure . Hesperidin successfully induced PGC1‐α levels suggesting its ability to increase mitochondrial ATP content and improve respiration . The extensive histopathological score in colonic tissue with decreased bcl2 expression in UC group may be due to a concomitant increase in apoptosis and decreased antiapoptotic proteins including bcl2 at an early phase of colitis, which might lead to epithelial barrier function breakdown .…”

8 Weeks of 2s-Hesperidin Supplementation Improves Power Output at Estimated Functional Threshold Power and Maximum Power in Amateur Cyclist

“…The effect of long-term intake of hesperidin has also been investigated in animal studies. Biesemann et al [13] observed that 6-weeks of hesperetin supplementation (main metabolite of hesperidin) (50 mg•kg -1 •d -1 ) improved running performance (exercise time) in aged mice. De Oliveira et al [14] found that four weeks of hesperidin consumption (100 mg/kg body mass) enhanced the antioxidant capacity in the continuous swimming group (183%) and decreased the lipid peroxidation (TBARS) in the interval swimming group (-45%) in rats.…”

“…Based on the understanding behind the mechanism of hesperidin in vitro, as well as the scientific evidence presented above, hesperidin is a good candidate for improving performance. Hesperidin strongly increases intracellular ATP compared to the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), even when AICAR concentration has been increased by 10-fold (100 µM) [13]. In addition, hesperetin (10 µM) has been shown to increase intracellular ATP by 33% and mitochondrial spare capacity by 25%, as well as establish an antioxidant state.…”