Curcumin as a Therapeutic Agent for Sarcopenia

Sarcopenia is the progressive loss of muscle mass, strength, and functions as we age. The pathogenesis of sarcopenia is underlined by oxidative stress and inflammation. As such, it is reasonable to suggest that a natural compound with both antioxidant and anti-inflammatory activities could prevent sarcopenia. Curcumin, a natural compound derived from turmeric with both properties, could benefit muscle health. This review aims to summarise the therapeutic effects of curcumin on cellular, animal, and human studies. The available evidence found in the literature showed that curcumin prevents muscle degeneration by upregulating the expression of genes related to protein synthesis and suppressing genes related to muscle degradation. It also protects muscle health by maintaining satellite cell number and function, protecting the mitochondrial function of muscle cells, and suppressing inflammation and oxidative stress. However, it is noted that most studies are preclinical. Evidence from randomised control trials in humans is lacking. In conclusion, curcumin has the potential to be utilised to manage muscle wasting and injury, pending more evidence from carefully planned human clinical trials.


Introduction
One in six individuals worldwide will be 60 years or older by 2030. The number of individuals 60 years and older worldwide is expected to increase from 1 billion in 2020 to 2.1 billion in 2050. By 2050, 426 million people will be 80 years or older [1]. Sarcopenia is often considered an important factor in senior frailty and mobility loss. It is characterised by decreased muscle mass, strength, and functionality with age [2][3][4][5][6][7][8]. An estimation in 2019 suggested that the economic burden of sarcopenia-associated disability was USD 40.4 billion in the United States, with an average cost of USD 260 per person. These expenses include hospitalisation, nursing home admissions, and home healthcare costs [9]. In addition to disability, sarcopenia is associated with multiple comorbidities, such as osteoporosis [10], obesity [11], and type II diabetes mellitus [12].
To effectively prevent sarcopenia, it is essential to have a thorough understanding of its pathophysiology and to use this knowledge to develop appropriate treatment strategies. The pathogenesis of sarcopenia includes impaired myofiber metabolism and adverse changes to muscle satellite cells, which lead to defective myogenesis and the loss of skeletal muscle homeostasis [13]. The reductions in muscle quality and strength associated with sarcopenia are also accompanied by neurological impairments affecting motor neurons and neuromuscular junctions, which result in denervated muscle fibers [14]. Additionally, persistent low-grade inflammation, poor anabolic signaling mediated by the growth hormone (GH)/insulin growth factor-1 (IGF-1) pathway, lower protein consumption, and vitamin D deficiency all contribute to the deterioration of muscle quality with age [15][16][17]. are discussed. We hope this review will encourage interested researchers to investigate the use of curcumin as an interventional agent for sarcopenia and serve as a springboard for clinical studies on humans.

Therapeutic Effects of Curcumin on Muscle Health
Curcumin has been linked to a plethora of health advantages, including muscle health, in various studies [49]. Preserving muscle mass during ageing is the most important step in preventing sarcopenia. Receno et al. (2019) reported that curcumin (0.2% diet for 4 months) increased the muscular mass of supplemented rats without altering the body mass of 32-month-old male F344xBN rats, which is in line with previous studies [50][51][52][53]. In another study on contusion-induced muscular injury, 5 mg/kg body weight of curcumin for 7 days in 8-week-old male ICR mice was shown to dramatically enhance muscle mass. Similarly, curcumin supplementation boosted muscle mass but it had no discernible effect on body weight [54]. The higher skeletal muscle mass of curcumin-supplemented rats was consistent with earlier studies using various models of muscle wasting, by reducing both oxidative stress and inflammation [55,56].
The animals showed improved strength as a result of increased muscle strength. In a study, treatment of 150 mg/kg curcumin for over a period of 2 months resulted in improved muscle endurance, grip strength, and fat/lean mass ratio in 12-month-old male Sprague Dawley rats with LPS-induced sarcopenia [57]. Curcumin (40 and 80 mg/kg) administered 30 min before forced exercise for 28 days could complement exercise-based therapy to prevent muscular issues such as sarcopenia by regulating the expression of genes related to protein synthesis, apoptosis, and inflammation in chronic forced exercise executed 10month-old ICR mice [58]. The effects of curcumin on muscle health are summarised in Table 1.

Mechanisms of Curcumin in Preserving Muscle Health
The beneficial effects of curcumin on muscle health are based on several mechanisms. Sani et al. (2021) investigated the protective effects of curcumin on dexamethasone-induced muscle atrophy using differentiated C2C12 cells. It was reported that curcumin treatment decreased Atrogin-1 and MuRF-1 expression, which inhibits protein degradation. It also increased the phosphorylation level of Akt, which is a vital protein in the mTOR signaling pathway which activates protein synthesis and inhibits protein degradation [59]. Gorza et al. (2021) demonstrated that curcumin, given to 18-month-old C57BL6J and C57BL10ScSN male mice for 6 months at a dose of 120 µg/kg, significantly increases satellite cell commitment and recruitment to delay the onset of pre-sarcopenia and sarcopenia. This was evident by the increased proportion of isolated MyoD-positive satellite cells from aged hindlimb muscles and sustained myofiber development in the ageing soleus muscle [49]. These mechanisms will be elaborated further in the following sections.

Effects of Curcumin on Satellite Cells
Sarcopenia is speculated to develop due to satellite cell malfunction and depletion [60]. Sarcopenia affects the ability of the elderly to restore muscular function by reducing the functionality of satellite cells [61]. Satellite cell loss reduces the ability of sarcopenic muscles to recuperate in old age and contributes to muscular fibrosis in response to injury [62]. Sarcopenia affects satellite function and maintenance, and throughout a person's lifetime, reduces the ability of the muscle to regenerate new tissue and maintain tissue homeostasis [60].
Chronic inflammation harms satellite cells' function in muscle regeneration [63]. This observation may be caused by the activation of the nuclear factor-κB (NF-κB) pathway in satellite cells [64]. This observation may be caused by the activation of the nuclear factor-κB (NF-κB) pathway in satellite cells [65], and inhibits the NF-κB pathway, thereby attenuating muscle protein degradation in other disease models such as sepsis [66,67].
In a recent study, treating immobilised 10-week-old C57BL/6J mice with 1 mg/kg body weight curcumin for 7 days demonstrated a significant improvement in the numbers of muscle progenitor cells, quiescent, activated, and total satellite cell counts in the limb muscles compared to non-treated immobilised animals [68]. In agreement with this, it has previously been demonstrated that upregulation of sirtuin-1 maintains satellite cells in a condition resembling stem cells. The increase in the quantity of quiescent and total satellite cells observed in the muscles of the unloaded animals treated with curcumin was most likely caused by this effect [69]. These results collectively imply that curcumin favors muscle regeneration after unloading. The effects of curcumin on satellite cells of the muscle are shown in Table 2. Table 2. The effects of curcumin on muscle cells.

Author (Years) Study Design Major Findings Conclusion
Grabowska et al., 2016 [65] Cells senescing in a replicative and premature manner were exposed to curcumin at low doses (0.

Effects of Curcumin on Mitochondrial Function
Mitochondria support energy equilibrium of the skeletal muscle through adaptive reprogramming in response to demands imposed by a variety of physiologic or pathological situations. Hamidie et al. (2015) demonstrated that the combination of curcumin therapy and endurance training could increase mitochondrial biogenesis in skeletal muscle via increasing cAMP levels [71]. In a different study, curcumin inhibited the activity of glycogen synthase kinase-3 (GSK-3) and was demonstrated to be useful in preventing muscular atrophy and mitochondrial dysfunction caused by chronic kidney disease (CKD). In the muscle of 6-7-week-old male C57BL/6 mice with CKD, GSK-3 deletion promoted mitochondrial biogenesis, decreased mitochondrial oxidative damage, and enhanced mitochondrial function. This study found that a diet containing 0.04% (w/w) curcumin treatment for 12 weeks prevented skeletal muscle GSK-3 activity, reducing the oxidative damage and dysfunction brought on by CKD in the mitochondria [72]. Another study using a mouse myoblast C2C12 cell line treated with low-dose (1, 2 and 5 uM) and high-dose (10, 20 and 50 uM) curcumin, discovered that curcumin might be an effective treatment for diabetes and other mitochondrial diseases when used in modest dosages (5 uM) [73]. In a separate study, it was demonstrated that curcumin supplementation of 100 mg/kg body weight for 3 days significantly increased the activity of mitochondrial enzymes cytochrome c oxidase, succinate dehydrogenase, Na+/K+-ATPase, and Ca2+-ATPase in the skeletal muscle mitochondria of rats with chronic obstructive pulmonary disease (COPD) [74]. The effects of curcumin on the mitochondrial function of the muscle are shown in Table 3. Table 3. The effects of curcumin on mitochondrial function of the muscle.

Effects of Curcumin on Low-Grade Inflammation
Evidence has shown that chronic low-grade inflammation led to sarcopenia because it influences both muscle protein production and breakdown through several signaling pathways [34]. Low-grade inflammation is, at least in part, a result of an increase in the number of cells that exit the cell cycle and enter cellular senescence [34]. A previous study on C2C12 cells treated with 100 ug/mL Cur-SHAP showed decreased levels of IL-6 and TNF-α, suggesting that curcumin may inhibit inflammation induced by LPS [57].
In another study, 80 women with moderate physical levels given oral curcumin supplementation of 500 mg/day for 8 weeks showed a considerable drop in CRP and lactate dehydrogenase (LDH) levels, which is a marker for muscle and tissue damage. Additionally, curcumin administration also reduced MDA significantly, which had a favorable impact on oxidative stress [75]. This shows that there are very limited studies on the anti-inflammatory effect of curcumin on skeletal muscle health, and more research should be conducted to learn more about it. The effects of curcumin on inflammation and muscle health in humans are shown in Table 4.

Effects of Curcumin on Oxidative Stress
The redox status of our bodies is regulated by various antioxidant enzymes that break down potential oxidants. Superoxide dismutase (SOD) converts superoxide into H 2 O 2 and O 2 [76]. Catalase produces non-toxic H 2 O and O 2 , with H 2 O 2 produced by SOD [77]. Additionally, glutathione peroxidase (GPx) transforms reduced glutathione and H 2 O 2 into glutathione disulfide and H 2 O [78]. Unremoved ROS react with polyunsaturated fatty acids to form lipid peroxidation, which results in MDA production [79]. A rise or fall in the ROS level can be verified by monitoring the MDA level and antioxidant enzyme activity.
Increased oxidative stress in skeletal muscle is a hallmark of ageing, which can disrupt cellular redox control, alter transcription factor activity, and damage cellular macromolecules such as proteins, lipids, and DNA [80]. Age-related changes in oxidative load may be brought about by increasing oxidation, diminished antioxidant defenses, or a combination of these factors [80]. For instance, aged skeletal muscle produced more ROS and reactive nitrogen species, whereas the antioxidant state of the human vastus lateralis decreased, indicating a degraded functional response [81]. A study on dexamethasoneinduced (DEX) sarcopenia reported that DEX increases ROS to produce muscle atrophy [82].
Curcumin intake has been shown to increase antioxidant enzyme activities and decrease the levels of MDA [83]. A prior study using C2C12 cells treated with 1 ug/mL lipopolysaccharides (LPS) to stimulate inflammation and then treated with 100 ug/mL curcumin stearic acid (Cur-SHAP) after 24 h showed that ROS levels in the Cur-SHAP group were lower than that in the LPS group, which confirmed that Cur-SHAP exhibits good antioxidant effects [57]. In a separate study, C2C12 myoblasts were treated with turmeric hot water extract at 100, 250, 500, 750, and 1000 ug/mL concentrations for 24 h [84]. The study reported that curcumin treatment reduced intracellular ROS levels in the H 2 O 2 -induced cells, suggesting that curcumin might have the ability to protect oxidative stress-induced C2C12 myoblasts [84].
Kim S. et al. conducted a study of dexamethasone-induced sarcopenia in ICR mice fed with curcumin water extract for 1 week, which reported that myostatin, MuRF-1, and Atrogin-1 expression levels were decreased, thus preventing muscle loss. Additionally, the study also reported that curcumin boosted the antioxidant enzyme activity while lowering MDA levels [83]. The transcription factor nuclear factor erythroid-2 related-factor-2 (Nrf2) is the "master transcriptional regulator" of the body's antioxidant defenses [85]. When the production of ROS is enhanced, Nrf2 binds to the antioxidant response element (ARE) and increases the expression of the genes for antioxidant enzymes [86]. Numerous studies have linked the dysregulation of Nrf2 with ageing and enhanced oxidative stress, decreased antioxidant response, and muscle deterioration. Therefore, activating Nrf2 and reducing oxidative stress would benefit the ageing skeletal muscle [87][88][89]. Curcumin can neutralise free radicals directly, and encourage nuclear translocation and Nrf2 activation via separation from the kelch-like ECH-associated protein 1 (Keap1) [90]. He et al. (2012) found that after 15 days of 50 mg/kg body weight curcumin treatment in a mouse model of high-fat diet-induced insulin resistance, muscular Nrf2 activation was greater compared to untreated controls [91]. In another study, 32-month-old F344xBN male rats given a 0.2% curcumin-supplemented diet for 4 months showed that curcumin increases levels of Nrf2. Additionally, curcumin also significantly lowered 3-nitrotyrosine (3-NT) and protein carbonyls (PC) levels [53]. The evidence of curcumin improving muscle health through oxidative stress regulation is shown in Table 5. The mechanism effect of curcumin is summarised in Figure 1.

Conclusions
There are no effective pharmaceutical treatments for sarcopenia at this moment [93]. The existing evidence shows that curcumin can be a potential alternative treatment for managing sarcopenia. It achieves muscle protection by maintaining satellite cell number and function, protecting the mitochondrial function of muscle cells, as well as suppressing inflammation and oxidative stress. However, more studies should be conducted on the delivery route, exact dose, and mechanisms of action of curcumin on sarcopenia. Its muscle protective functions should be verified in well-planned human clinical trials to ensure efficacy and safety in humans.