Sarcopenia, the progressive and generalized loss of skeletal muscle mass and function with age, represents a major contributor to frailty, disability, and reduced quality of life in the elderly. Its pathophysiology is multifactorial, encompassing cellular, molecular, and systemic alterations. Mechanistically, sarcopenia is driven by satellite cell dysfunction, impaired regenerative capacity, mitochondrial decline, chronic low-grade inflammation, neuromuscular junction instability, and dysregulated proteostasis involving the ubiquitin-proteasome and autophagy- lysosome systems. Additional factors such as hormonal decline, oxidative stress, altered myokine signaling, and fiber-type transitions further exacerbate skeletal muscle atrophy. These interlinked processes collectively result in impaired muscle plasticity, reduced contractile strength, and progressive degeneration of type II fibers. Given the complexity of its mechanisms, nutritional interventions, particularly dietary supplements and natural products, have attracted considerable attention as potential modulators of sarcopenia. Hence, in the present study, the literature was scanned using standard databases and keywords related to 'natural products and diet used in sarcopenia' to identify research papers and reviews that were reviewed to compile the present review. It was found that some bioactive compounds, including polyphenols (such as resveratrol and curcumin), flavonoids (such as quercetin and catechins), omega-3 fatty acids, essential amino acids, and plant-derived adaptogens, exhibit antioxidant, anti-inflammatory, and mitochondrial- protective effects. These nutraceuticals not only counteract oxidative and inflammatory damage but also enhance anabolic signaling, mitochondrial biogenesis, and neuromuscular stability, thereby supporting muscle preservation and functional recovery. Emerging evidence suggests that combining such natural compounds with adequate protein intake and exercise may synergistically mitigate sarcopenia-induced skeletal muscle atrophy. This review consolidates current mechanistic insights into sarcopenia and critically evaluates the role of dietary supplements and natural products as promising, safe, and accessible interventions. Understanding the interplay between molecular pathways and nutritional modulation provides a foundation for developing effective strategies to combat age-related muscle decline.

Calpains (CAPN) serve a crucial function in the regulation of NF-κB activity within skeletal muscle by mediating the degradation of IκBα, facilitating NF-κB activation, inhibiting apoptosis through the suppression of c-FLIP, modulating the activity of p65, p52, and p50, and enhancing the expression of its inhibitor, cardiac ankyrin repeat protein, among other roles. Through these coordinated actions, CAPNs fine-tune inflammatory and survival signaling in muscle cells. The lack of CAPNs leads to increased apoptotic myonuclei and a range of pathological conditions, including muscle weakness, impaired regeneration, and enhanced susceptibility to stress-induced damage. The multifaceted role of CAPNs in modulating NF-κB activity in skeletal muscle constitutes a complex and vital aspect of cellular signaling pathways. CAPNs function as both primary and alternative cleavage agents, modifying diverse proteins that modulate NF-κB signaling. This dual role allows CAPNs to act as both activators and modulators of NF-κB-dependent transcriptional responses. The intricate interplay between CAPNs and NF-κB highlights the importance of maintaining appropriate regulation and equilibrium in skeletal muscle function, particularly in response to stressors such as physical exercise or injury. Dysregulation of this balance may contribute to chronic inflammation, muscle atrophy, and degenerative muscle disorders. Elucidating the molecular mechanisms underlying the crosstalk between calpains and NF-κB may yield significant insights for the formulation of therapeutic strategies targeting disease conditions associated with skeletal muscle. Targeting CAPN-NF-κB signaling may therefore represent a promising approach to mitigate muscle degeneration and improve muscle health under pathological conditions.

Tinospora cordifolia (Willd.) Miers (Menispermaceae), an important medicinal plant in Ayurvedic medicine, is traditionally used as a rejuvenating tonic and immune modulator. Its alkaloids (Alk) and terpenoids (Terp) possess antioxidant and anti-inflammatory properties, suggesting that it may be beneficial in preventing sarcopenia-induced muscle degeneration. This study aimed to evaluate the efficacy of T. cordifolia-derived Alk and Terp in the treatment of sarcopenia in aged mice. Male Swiss albino mice, 10 months old, were administered Alk and Terp for the next 8 months. Muscle tissues were analyzed for the makers of sarcopenia, oxidative stress, inflammation, apoptosis, myogenesis, and histological changes. Aged control mice showed similar to 2.0-fold increases in oxidative stress and inflammatory cytokines, elevated MuRF-1 and Atrogin-1, reduced p-AktSer473, and decreased myogenic marker expression. Alk and Terp supplementation significantly reduced oxidative stress and inflammation, downregulated MuRF-1 and Atrogin-1, restored p-AktSer473 (similar to 1.6-fold), and enhanced PGC-1 alpha, HSP70, Myogenin, MyoD, and Pax7 (similar to 2.5-fold). Bax expression was reduced, indicating decreased apoptosis. Histology revealed preserved muscle fiber architecture, larger cross-sectional area, improved mitochondrial density, and reduced fiber type switching. All the findings were correlated with the decrease of sarcopenic markers, i.e., Bmp-7, Atf4, and Gadd45. Metformin showed comparatively modest effects. Alk and Terp from T. cordifolia reduce sarcopenia symptoms in aged mice by modulating Akt activity, inhibiting apoptosis, oxidative stress, and inflammation, and promoting myogenesis. Overall, Terp was more effective at reducing inflammation than alkaloids. Conversely, Alk increased Akt phosphorylation and, consequently, activity levels compared to Terp.

AKT (protein kinase B, PKB) coordinates the balance between anabolic and catabolic signaling in skeletal muscle through distinct ubiquitin chain types. Some E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs) form stable binary complexes via non-catalytic interfaces, adding a regulatory layer unavailable to either enzyme alone. This mechanistic synthesis review presents a systematic literature analysis (inception to May 2026; 26 eligible studies). It identified four E3-DUB pairs proposed to regulate AKT in skeletal muscle. These are TRAF6-CYLD (plasma-membrane K63-ubiquitination), MUL1-USP9X (mitochondrial K48-ubiquitination of AKT2), CHIP-UCH37 (proteasome-proximal quality control), and SCF-Skp2-USP37 (PHLPP1/2-dependent control of AKT Ser473 phosphorylation). All four interfaces are structurally separate from the catalytic sites and are regulated by upstream kinase phosphorylation. Evidence for the four pairs is markedly uneven. TRAF6-CYLD is supported by endogenous co-immunoprecipitation and functional data in muscle models. CHIP and UCH37 each act on AKT-related substrates independently and are individually well documented, but a direct CHIP-UCH37 interaction has not itself been demonstrated. SCF-Skp2-USP37 interaction data rest on a real but non-muscle direct interaction, whereas MUL1-USP9X has no reported direct interaction at all; CHIP-UCH37, SCF-Skp2-USP37, and MUL1-USP9X are therefore all presented as testable hypotheses of varying strength. In chronic atrophy, available data are consistent with disruption of these complexes contributing to AKT suppression through parallel, largely independent mechanisms. However, simultaneous disruption of all four has not been demonstrated in a single system. Available gene expression and protein datasets from sarcopenic muscle broadly support these predictions, though direct experimental validation in human tissue remains pending. This complex-centric framework recasts AKT ubiquitination as an integrated regulatory framework. Each structurally autonomous interface may represent a potentially distinct target for muscle-wasting conditions that currently lack approved therapies.

Background: Sarcopenia refers to a progressive decline in muscle mass and strength, primarily caused by increased oxidative stress and chronic low-level inflammation associated with aging. Tinospora cordifolia (TC) and Terminalia chebula (TCH) have been extensively utilized in Ayurvedic medicine due to their evident antioxidant and anti-inflammatory attributes; hence, they may prove beneficial in mitigating the progression of sarcopenia. Methods: TC and TCH were administered as supplements over an 8-month period to 10-monthold mice. The levels of oxidative stress, inflammation, and sarcopenia markers were assessed using biochemical assays, quantitative PCR, and Western blotting. The integrity of muscular tissue was evaluated through histological, wet muscle, and body mass analysis. Results: The TC and TCH interventions elevated the levels of Akt1 and Pgc-1α (~2.0-fold) and diminished muscle atrophy markers (Atf4, Fbxo32, Trim63), pro-inflammatory cytokines (Il6, Il1β, Tnfα), and modulated apoptotic markers (Bax and Bcl2) in aged mice, hence maintaining levels near those of younger controls. Furthermore, the interventions of TC, TCH, and their synergistic application effectively sustained the expression of myogenic factors, namely Myod and Myog, and of sarcopenia markers, such as Atf4, Gadd45α, Bmp-7, and Hspa1b, at levels akin to those of young controls, showing negligible declines. These findings were corroborated with significantly enhanced fiber compactness, cross-sectional area, mitochondrial content, and reduced fiber type switching in aged mice. discussion: - Discussion: TC and TCH effectively mitigated the oxidative burden and inflammation and upregulated myogenesis in aged mice. Conclusion: TC and TCH may serve as therapeutic options to address sarcopenia-induced muscle wasting and need clinical trials.

Skeletal muscle (SkM) atrophy results from metabolic disorders causing body and muscle mass loss, affecting morbidity and mortality. Increased oxidative stress, inflammation, and poor prognosis are the leading causes of involuntary weight loss. Ursolic acid (UA), known for its antioxidant and anti-inflammatory properties, can potentially reduce oxidative stress and inflammation in muscles, but its effects on muscle mass regulation are still unknown. Therefore, present study investigated the medicinal efficacy of UA and its mode of action against murine model of SkM atrophy over 7 days of UA supplementation. Denervation-induced SkM atrophy significantly impacts both overall body weight and the weight of individual muscles (p < 0.05). However, supplementation with UA can effectively counteract these effects by promoting the synthesis of the slow-myosin heavy chain, thereby restoring body weight and myotube diameter. Moreover, UA also plays a crucial role in reducing the production levels of reactive oxygen species (ROS), lipid peroxidation (LPO), and caspase-3-like activity in atrophied muscles. UA also, prevents the leakage of creatine kinase (CK) through the upregulation of superoxide dismutase (SOD) and glutathione peroxidase (GPx) expression. Furthermore, the results obtained from qRT-PCR demonstrated a significant decrease in the levels of proinflammatory markers, namely IL-1β, IL-6, TNF-α, and TWEAK, approximately four-fold after the third day of the UA intervention. UA also upregulated PGC-1α, Bcl2, and Akt expression for maintenance of redox homeostasis.

Sciatic nerve injury leads to molecular events that cause muscular dysfunction advancement in atrophic conditions. Nerve damage renders muscles permanently relaxed which elevates intracellular resting Ca2+ levels. Increased Ca2+ levels are associated with several cellular signaling pathways including AMPK, cGMP, PLC-β, CERB, and calcineurin. Also, multiple enzymes involved in the tricarboxylic acid cycle and oxidative phosphorylation are activated by Ca2+ influx into mitochondria during muscle contraction, to meet increased ATP demand. Nerve damage induces mitophagy and skeletal muscle atrophy through increased sensitivity to Ca2+-induced opening of the permeability transition pore (PTP) in mitochondria attributed to Ca2+, ROS, and AMPK overload in muscle. Activated AMPK interacts negatively with Akt/mTOR is a highly prevalent and well-described central pathway for anabolic processes. Over the decade several reports indicate abnormal behavior of signaling machinery involved in denervation-induced muscle loss but end up with some controversial outcomes. Therefore, understanding how the synthesis and inhibitory stimuli interact with cellular signaling to control muscle mass and morphology may lead to new pharmacological insights toward understanding the underlying mechanism of muscle loss after sciatic nerve damage. Hence, the present review summarizes the existing literature on denervation-induced muscle atrophy to evaluate the regulation and expression of differential regulators during sciatic damage.

Skeletal muscle atrophy is an inevitable sequel of various factors such as cachexia, aging, fasting, denervation, and microgravity. It is characterized by reduced muscle protein through increased proteolysis and decreased protein synthesis. Recent research suggests that atrophy can significantly contribute to mortality among afflicted persons, and the hindrance of muscular deterioration is expected to extend lifespan. Programmed cell death or apoptosis is imperative for preserving the integrity of proliferative tissues. However, the exact role of apoptosis in post-mitotic tissues, such as skeletal muscle, remains less well-defined. Within the context of muscle atrophy, apoptosis occurs in both myonuclei as well as other types of muscle cells. The loss of muscle mass is likely attributed to the apoptotic demise of myonuclei, yet the mechanisms driving this process remain largely unknown. Both caspase-dependent and caspase-independent pathways have been implicated, with the specific mode of atrophy induction determining the apoptotic mechanisms utilized. Furthermore, it is still undetermined whether a reduction in apoptosis will ameliorate atrophy, necessitating distinct research strategies for various causes of skeletal muscle loss.

Skeletal muscle (SkM) mass loss is directly related to increased oxidative stress, inflammation, and muscle protein degradation mediated by proteolytic systems. Growing evidence suggests the interdependency of autophagy and UPS in the progression of SkM atrophy. Hence, the current study was performed to understand the interdependency of autophagy and UPS and their impact on SkM atrophy. 6-week-old male Wister rats undergone denervation were randomized into different treated groups for one week alone and in conjunction with UPS and autophagy inhibitors. Further assessments were achieved by morphological aberration (via histopathology), mRNA (via RT-qPCR), protein expression of muscle-specific markers (via western blotting), calpain activity (via Zymography) and biochemical alteration. In denervated rats, treatment mainly with chloroquine and somehow with velcade tried to normalize the activity of mitochondrial complex I and IV, calpains activity, levels of ROS, pro-atrophic markers TWEAK, FoxO3, NFkB, Smad3/4, UPS promoting E3 ligases; Atrogin1, MuRF1, autophagy promoting factors; LC3β, Atg5, p62, LAMP2A, PINK1 and myosin heavy chain. In denervated skeletal muscles, inhibition of autophagy affects the activity of proteasome and vice versa. Hence, autophagy and UPS both are interdependent systems in SkM atrophy. Autophagy inhibition attenuates muscle atrophy more precisely than proteasomal and both systems inhibitions.

Skeletal muscles are considered the largest reservoirs of the protein pool in the body and are critical for the maintenances of body homeostasis. Skeletal muscle atrophy is supported by various physiopathological conditions that lead to loss of muscle mass and contractile capacity of the skeletal muscle. Lysosomal mediated autophagy and ubiquitin-proteasomal system (UPS) concede the major intracellular systems of muscle protein degradation that result in the loss of mass and strength. Both systems recognize ubiquitination as a signal of degradation through different mechanisms, a sign of dynamic interplay between systems. Hence, growing shreds of evidence suggest the interdependency of autophagy and UPS in the progression of skeletal muscle atrophy under various pathological conditions. Therefore, understanding the molecular dynamics and associated factors responsible for their interdependency is necessary for the new therapeutic insights to counteract muscle loss. Based on current literature, the present review summarizes the factors that interplay between autophagy and UPS in favor of enhanced proteolysis of skeletal muscle and how they affect the anabolic signaling pathways under various conditions of skeletal muscle atrophy.

Tinospora cordifolia (Hindi name giloy), a medicinal plant known to have anabolic and rejuvenating properties, has been reported to contain various kinds of phytoecdysteroids. The interspecific interactions of T. cordifolia with different plants are known to change its chemotypes, so the variations in phytoecdysteroids due to interspecific interactions with other plants need to be explored. The effect of interspecific interactions on phytoecdysteroid contents was explored in the current study using HPLC-Q-TOF-MS. Initial analysis of mass data based on characteristic fragment ions and loss of multiple water molecules validated the presence of 10 phytoecdysteroids and 4 derivatives across the samples screened. Principle component analysis (PCA) and partial least square discriminant analysis (PLS-DA) showed significant (p>0.05) variations in patterns of phytoecdysteroid due to interspecific interactions. Statistical analysis revealed that T. cordifolia having interactions with Albizia lebbeck (Saras), and Acacia nilotica (Babool) formed separate distant groups, whereas. T. cordifolia having interactions with Azadirachta indica (Neem) is the most distant group. T. cordifolia co-occurred with A. indica showed the highest number of up-regulated phytoecdysteroids. Fold change analysis showed that interspecific interactions of T. cordifolia with A. indica increased the contents of 3-dehydroecdysone (2-fold), makisterone A (4.8-fold), 24-methylshidasterone (4.3-fold), 1-hydroxy-20,22-didehydroxysterone (2-fold), 1-hydroxy-22-deoxy-20,21-dehydroecdysone (2-fold), cycleasterone A (3.3-fold), and 3 beta,5 alpha,14 alpha-trihydroxyergosta-7,22-diene-6-one (2.5-fold) in comparison to other plants. Selectively increased levels of 4-dehydro-20-hydroxyecdysone (>= 4.0 fold) and 24-methylshidasterone in the plant having interactions with Tamarindus indica, and Ficus benghalensis, respectively were observed.

Objective: Detailed analysis of un-processed and un-derivatized free and conjugated urinary steroids is useful to avoid miscalculations and to diagnose sports doping and adrenal problems, including abnormal steroidogenesis, congenital deficiency of related enzymes, cancer, and other disease conditions. Hence, the present study was conducted to develop a soft ionization method to identify the maximum number of urinary steroids using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometer (HPLC–Q-TOF-MS). Material and Methods: HPLC–Q-TOF-MS was carried out for the qualitative detection of steroids and their conjugates in urine samples. The method provides high sensitivity and fast analysis of steroids and their glucuronides without hydrolysis or sample preparation or extraction of steroids. Results: Using the method, 44 steroids belonging to C-18, C-19, and C-21 classes and their conjugates were resolved and identified using positive and negative modes of ionizations by their characteristic ionization and collision energy induced dissociation behaviors. Conclusion: The method is time-saving and good to compare samples from different peoples with control or healthy ones as it does not require any kind of pre-treatment or sample processing. It provides a complete picture of steroids metabolism and catabolism. It can be good for doping control or to explore the effects of other drugs. However, in qualitative analysis, one may miss the significant information unless direct methods of steroids analysis to be employed.

The skeletal muscle (SkM) is the largest organ, which plays a vital role in controlling musculature, locomotion, body heat regulation, physical strength, and metabolism of the body. A sedentary lifestyle, aging, cachexia, denervation, immobilization, etc. Can lead to an imbalance between protein synthesis and degradation, which is further responsible for SkM atrophy (SmA). To date, the understanding of the mechanism of SkM mass loss is limited which also restricted the number of drugs to treat SmA. Thus, there is an urgent need to develop novel approaches to regulate muscle homeostasis. Presently, some natural products attained immense attraction to regulate SkM homeostasis. The natural products, i.e., polyphenols (resveratrol, curcumin), terpenoids (ursolic acid, tanshinone IIA, celastrol), flavonoids, alkaloids (tomatidine, magnoflorine), vitamin D, etc. exhibit strong potential against SmA. Some of these natural products have been reported to have equivalent potential to standard treatments to prevent body lean mass loss. Indeed, owing to the large complexity, diversity, and slow absorption rate of bioactive compounds made their usage quite challenging. Moreover, the use of natural products is controversial due to their partially known or elusive mechanism of action. Therefore, the present review summarizes various experimental and clinical evidence of some important bioactive compounds that shall help in the development of novel strategies to counteract SmA elicited by various causes.

Hypertriglyceridemia (HTG) is strongly associated with the various types of disease conditions and evolving as epidemics. Hence, it is important to identify molecules that lower the triglyceride and chylomicron levels. Tinospora cordifolia is an illustrious Ayurveda drug, has proved juvenile and immunomodulatory properties. Twenty four (24) patients having >499 mg/dL TG and 130–230 mg/dL of cholesterol were randomized and given 100 mL/day (~3.0 g) water extract of T. cordifolia (TCE) for 14 days. Basal parameters were analyzed before and after TC intervention to analyzed primary outcomes. Further, unbiased metabolomics and proteomics profiling was explored to assess the efficacy of TCE in HTG patients. TCE intervention decreased the levels of triglycerides, and VLDL to 380.45 ± 17.44, and 31.85 ± 5.88, and increased the HDL levels to 47.50 ± 9.05 mg/dL significantly (p < 0.05). Metabolomics analysis identified the significant alteration in 69 metabolites and 72 proteins in plasma of HTG patients. TCE intervention reduced the level of isoprostanes, ROS, BCAA, and fatty acid derivatives, significantly. The annotation databases, Metboanalyst predicted Akt and Rap1 signaling, and ECM-receptor interaction is the most affected in HTG patients. TCE intervention normalized these events by increasing the peroxisome biogenesis and modulating Akt and Rap1 signaling pathway. T. cordifolia intervention suppresses the baseline in HTG patients. Omics analysis showed that TCE intervention modulates the Akt and Rap signaling, and peroxisome biogenesis to control the cellular switches and signaling pathways. Hence, TCE can be used as a supplement or alternate of standard drugs being used in the management of HTG.

Gut microbiota broadly impacts human health, but urinary microbial metabolites remain largely undefined. The concentration of microbial metabolites can be directly correlated with microbial populations in the human gut to define disease states. Tinospora cordifolia (Willd.) Miers ex Hook. F. & Thoms is being used for ages in the Indian ayurvedic system of medicine and it has hypolipidemic and hypoglycaemic activity. Present study investigate the MS-based metabolomics variations of possible gut microbiota associated metabolites in hyperlipidemia (HPL) and HPL treated with Tinospora cordifolia extract (TCE) (TRT). Twenty-four HPL male patients and 10 age-matched controls (H LT) were enrolled. Early morning fasting blood and urine samples were collected on days 0 and 14th of TCE treatment and subjected to lipid profiling and Q-TOF-MS analysis. Multivariate analysis showed urinary levels of urocanic acid, hydroxyphenylacetate, linolenic acid, phenylpropionate, hypoxanthine, and indole acetate produced by Peptostreptococcs asaccharolyticus, Clostridium difficile, Faecalibacterium prausnitzii, Bifidobacterium, Subdoligranulum, Lactobacillus, Clostridium sporogenes, E. coli were depleted in HPL patients as compared to healthy controls. In contrast, levels of serotonin, acetylleucine, hippuric acid, and arabinitol were found to be increased (>2.0 fold, p<0.005). However, TCE treatment reverted the levels of these metabolites and therefore, gut microflora. Also, Cloacibacterium haliotis, Lactobacillus, Clostridium, and Bifidobacterium population decreased in HPL patients. Increased secretion of yeast or Candida albicans associated metabolites was because of their increased population. Hence, TCE treatment enhanced the growth of useful gut microbiota in hyperlipidemia patients.

Among the four proteolytic systems in the cell, autophagy and the ubiquitin-proteasome system (UPS) are the main proteolytic events that allow for the removal of cell debris and proteins to maintain cellular homeostasis. Previous studies have revealed that these systems perform their functions independently of each other. However, recent studies indicate the existence of regulatory interactions between these proteolytic systems via ubiquitinated tags and a reciprocal regulation mechanism with several crosstalk points. UPS plays an important role in the elimination of short-lived/soluble misfolded proteins, whereas autophagy eliminates defective organelles and persistent insoluble protein aggregates. Both of these systems seem to act independently; however, disruption of one pathway affects the activity of the other pathway and contributes to different pathological conditions. This review summarizes the recent findings on direct and indirect dependencies of autophagy and UPS and their execution at the molecular level along with the important drug targets in skeletal muscle atrophy.

Ethnopharmacological relevance: Tinospora cordifolia (TC) is being used as a blood purifier in Ayurveda since ancient time. It is a very popular immunomodulator and holds anti-inflammatory and anti-oxidative potential, hence anti-aging properties. Therefore, it is also known as 'Amrita' in Ayurveda and is widely used to treat diabetes mellitus type II (T2DM) and its secondary complications; however, its underlying mechanism was not expedited to date. Aim-: To explore the in vivo therapeutic efficiency and mechanism of action of TC and its secondary constitute magnoflorine on the skeletal muscle atrophy in the rat model of T2DM. Method: Animal model of T2DM was developed using streptozotocin (STZ) injection followed by intervention with TC, metformin, and magnoflorine for three weeks. Confirmation of T2DM and abrogation of atrophic markers and possible mechanisms on supplementation of TC and magnoflorine were explored using histology, bio-assays, Western blotting, and q-PCR. Result: TC and Magnoflorine supplementations significantly (p < 0.05) decreased the fasting blood glucose (FBG) levels in T2DM rats. Both treatments prevented the lean body, individual skeletal muscle mass, and myotubes diameter loss (p <= 0.05). Magnoflorine significantly reduced the degradation of the protein indicated by biochemical markers of atrophy i.e. decreased serum creatine kinase (CK) levels and increased myosin heavy chain-beta (MyHC-beta) levels in muscles. Q-PCR and western blotting supported the findings that magnoflorine significantly increased the mRNA and protein abundances (similar to 3 fold) of MyHC-beta.TC and magnoflorine efficiently decreased the expression of ubiquitin-proteasomal E3-ligases (Fn-14/TWEAK, MuRF1, and Atrogin 1), autophagy (Bcl-2/LC3B), and caspase related genes along with calpains activities in T2DM rats. Both TC and magnoflorine also increased the activity of superoxide dismutase, GSH-Px, decreased the activities of beta-glucuronidase, LPO, and prevented any alteration in the catalase activity. In contrast, magnoflorine increased expression of TNF-alpha and IL-6 whereas TC and metformin efficiently decreased the levels of these pro-inflammatory cytokines (p < 0.05). However, magnoflorine was found to increase phosphorylation of Akt more efficiently than TC and metformin. Conclusion: TC, and magnoflorine are found to be effective to control fasting blood glucose levels significantly in T2DM rats. It also promoted the Akt phosphorylation, suppressed autophagy and proteolysis that might be related to blood glucose-lowering efficacy of magnoflorine and TC. However, increased muscle weight, specifically of the soleus muscle, expression of IL-6, and slow MyHC indicated the increased myogenesis in response to magnoflorine and independent from its hypoglycemic activity.

Skeletal muscle atrophy has been characterized as a state of uncontrolled inflammation and oxidative stress that escalates protein catabolism. Recent advancement supports impinging signaling molecules in the muscle fibers controlled through toll-like receptors (TLR). Activated TLR signaling pathways have been identified as inhibitors of muscle mass and provoke the settings for muscle atrophy. Among them, mainly TLR2 and TLR4 manifest their presence to exacerbate the release of the pro-inflammatory cytokine to deform the synchronized muscle programming. The present review enlightens the TLR signaling mediated muscle loss and the interplay between inflammation and skeletal muscle growth.

Ethanopharmacological relevance: Tinospora cordifolia (TC) is widely being used as immunomodulatory and rejuvenile drug and well described in Indian Ayurveda system of medicine. Rejuvenation also means the fine tuning of the skeletal muscles. Skeletal muscle related disorder, i.e. atrophy is major problem which arise due to cachexia, sarcopenia and immobilization. However, despite of the great efforts, there is scarcity of FDA approved drugs in the market to treat skeletal muscle atrophy. Aim of the study: The current study was aimed to explore the in-vitro and in-vivo efficacy and mechanism of TC in myogenic differentiation and skeletal muscle atrophy to establish the possibility of its usage to counteract skeletal muscle atrophy. Materials and methods: C2C12 cell lines were used to determine myogenic potential and anti-atrophic effects of T. cordifolia water extract (TCE). Its in-vitro efficacy was re-validated in vivo by supplementation of TCE at a dose of 200 mg/kg/p.o. for 30 days in denervated mice model of skeletal muscle atrophy. Effects of TCE administration on levels of oxidative stress, inflammatory markers and proteolysis were determined. Results: TCE supplementation displayed increased lymphocyte proliferation and induced myogenic differentiation of C2C12 myoblasts by significantly increasing myocytes length and thickness, in comparison to control (p < 0.05). TCE supplementation decreased oxidative stress and inflammatory response by significantly modulating activities of catalase, glutathione peroxidase, lipid peroxidase, superoxide dismutase and beta-glucuronidase (p < 0.05). It increased MF-20c expression and ameliorated degradation of muscle protein by down-regulating MuRF-1 and calpain activity. Conclusion: TCE supplementation promotes myogenic differentiation in C2C12 cell lines and prevents denervation induced skeletal muscle atrophy by antagonizing the proteolytic systems (calpain and UPS) and maintaining the oxidative defense mechanism of the cell. Hence, TCE can be used as a protective agent against muscle atrophy.