Ursolic acid ameliorates hypobaric hypoxia‐induced skeletal muscle protein loss via upregulating Akt pathway: An experimental study using rat model

Abstract

Hypobaric hypoxic stress leads to oxidative stress, inflammation, and disturbance in protein turnover rate. Aggregately, this imbalance in redox homeostasis is responsible for skeletal muscle protein loss and a decline in physical performance. Hence, an urgent medical need is required to ameliorate skeletal muscle protein loss. The present study investigated the efficacy of ursolic acid (UA), a pentacyclic triterpene acid to ameliorate hypobaric hypoxia (HH)induced muscle protein loss. UA is a naturally occurring pentacyclic triterpene acid present in several edible herbs and fruits such as apples. It contains skeletal muscle hypertrophy activity; still its potential against HH-induced muscle protein loss is unexplored. To address this issue, an in vivo study was planned to examine the beneficial effect of UA supplementation on HH-induced skeletal muscle loss. Male Sprague Dawley rats were exposed to HH with and without UA supplementation (20 mg/kg; oral) for 3 continuous days. The results described the beneficial role of UA as supplementation of UA with HH exposure attenuated reactive oxygen species production and oxidative protein damage, which indicate the potent antioxidant activity. Furthermore, UA supplementation enhanced Akt, pAkt, and p70S6kinase activity (Akt pathway) and lowered the pro-inflammatory cytokines in HH exposed rats. UA has potent antioxidant and anti-inflammatory activity, and it enhanced the protein content via upregulation of Akt pathway-related proteins against HH exposure. These three biological activities of UA make it a novel candidate for amelioration of HH-induced skeletal muscle damage and protein loss.

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part I)

“…UA exhibited a suppressive effect against muscle wasting in induced chronic kidney disease both in vitro and in vivo; the phytocompound down-regulated the expression of myostatin and TNF-α, IL-1β, and IL-6 pro-inflammatory cytokines, led to the inhibition of ubiquitin E3 ligase, and decreased proteolysis [ 261 ]. Complementarily, UA counteracts hypobaric hypoxia-induced skeletal muscle protein loss through the up-regulation of the Akt signaling pathway, thus stimulating protein synthesis [ 262 ].…”

Antiinflammatory activity of natural triterpenes—An overview from 2006 to 2021

“…From this potential, interesting results in experimental models were acquired by Y. Zhang, Li et al (2020) for the treatment of multiple sclerosis, through the effect of ursolic acid demonstrated in immunomodulation and neural repair by direct remyelination in the chronic progressive stage of the disease, which currently does not have effective therapy. Recently, Rathor et al (2021) investigated the protective action of ursolic acid against muscle protein damage and loss induced by hypobaric hypoxia. An in vivo study was carried out and the effect of the compound supplementation attenuated the production of reactive oxygen species and the oxidative damage to proteins, indicating a strong antioxidant activity.…”

Role for Plant-Derived Antioxidants in Attenuating Cancer Cachexia

“…In addition to promising anti-cancer properties, UA was shown to improve skeletal muscle health in various pathologies ( Table 2 ). Acute (12 h) and short-term (three days) supplementation with UA attenuated muscle wasting induced by fasting [ 97 ] and hypobaric hypoxia, by promoting protein synthesis [ 98 ], attenuating protein degradation [ 97 ] and reducing oxidative stress [ 98 ]. Longer UA treatment (5–6 weeks) improved muscle mass and function and increased slow and fast muscle fiber size without altering fiber type composition [ 97 , 99 ].…”

“…Oral UA supplementation (20 mg/kg/day) for three days to healthy rats increased body mass and muscle protein content, in the absence of changes in pro-inflammatory cytokines, ROS levels or oxidation markers [ 98 ]. While the beneficial effects of UA on muscle have been established, higher doses of UA (200 mg/kg, twice daily via intraperitoneal injection) for seven days reduced body mass and cellular energy stores in aging, despite improved muscle regeneration and a fast-to-oxidative fiber type shift [ 101 , 102 ].…”

“…The attenuation of atrophy by UA is proposed to occur via induction of insulin-like growth factor-1 (IGF-1) and activation of Akt/mTOR1 signaling [ 97 , 100 ]. UA-mediated IGF-1 induction is localized to skeletal muscle, increasing muscle mass via Akt/mTOR signaling [ 99 ], evident from enhanced Akt and p70S6K phosphorylation and reduced glycogen synthase kinase 3β (GSK3β) expression [ 98 , 100 ]. While short-term UA treatment was insufficient to increase muscle IGF-1 content, it was able to enhance resistance exercise-induced activation of Akt/mTOR signaling [ 100 ].…”