Skeletal Muscle Proteolysis Research Articles

Metabolic Effects of Ketogenic Diets: Exploring Whole-Body Metabolism in Connection with Adipose Tissue and Other Metabolic Organs.

The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body's dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.

Myogenic microRNAs as Therapeutic Targets for Skeletal Muscle Mass Wasting in Breast Cancer Models.

Breast cancer is the type of cancer with the highest prevalence in women worldwide. Skeletal muscle atrophy is an important prognostic factor in women diagnosed with breast cancer. This atrophy stems from disrupted skeletal muscle homeostasis, triggered by diminished anabolic signalling and heightened inflammatory conditions, culminating in an upregulation of skeletal muscle proteolysis gene expression. The importance of delving into research on modulators of skeletal muscle atrophy, such as microRNAs (miRNAs), which play a crucial role in regulating cellular signalling pathways involved in skeletal muscle protein synthesis and degradation, has been recognised. This holds true for conditions of homeostasis as well as pathologies like cancer. However, the determination of specific miRNAs that modulate skeletal muscle atrophy in breast cancer conditions has not yet been explored. In this narrative review, we aim to identify miRNAs that could directly or indirectly influence skeletal muscle atrophy in breast cancer models to gain an updated perspective on potential therapeutic targets that could be modulated through resistance exercise training, aiming to mitigate the loss of skeletal muscle mass in breast cancer patients.

Renin angiotensin system-induced muscle wasting: putative mechanisms and implications for clinicians.

Renin angiotensin system (RAS) alters various mechanisms related to muscle wasting. The RAS system consists of classical and non-classical pathways, which mostly function differently. Classical RAS pathway, operates through angiotensin II (AngII) and angiotensin type 1 receptors, is associated with muscle wasting and sarcopenia. On the other hand, the non-classical RAS pathway, which operates through angiotensin 1-7 and Mas receptor, is protective against sarcopenia. The classical RAS pathway might induce muscle wasting by variety of mechanisms. AngII reduces body weight, via reduction in food intake, possibly by decreasing hypothalamic expression of orexin and neuropeptide Y, insulin like growth factor-1 (IGF-1) and mammalian target of rapamycin (mTOR), signaling, AngII increases skeletal muscle proteolysis by forkhead box transcription factors (FOXO), caspase activation and muscle RING-finger protein-1 transcription. Furthermore, AngII infusion in skeletal muscle reduces phospho-Bad (Ser136) expression and induces apoptosis through increased cytochrome c release and DNA fragmentation. Additionally, Renin angiotensin system activation through AT1R and AngII stimulates tumor necrosis factor-α, and interleukin-6 which induces muscle wasting, Last but not least classical RAS pathway, induce oxidative stress, disturb mitochondrial energy metabolism, and muscle satellite cells which all lead to muscle wasting and decrease muscle regeneration. On the contrary, the non-classical RAS pathway functions oppositely to mitigate these mechanisms and protects against muscle wasting. In this review, we summarize the mechanisms of RAS-induced muscle wasting and putative implications for clinical practice. We also emphasize the areas of uncertainties and suggest potential research areas.

LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice

Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.

Integrative profiling of metabolome and transcriptome of skeletal muscle after acute exercise intervention in mice.

This study aims to explore the molecular regulatory mechanisms of acute exercise in the skeletal muscle of mice. Male C57BL/6 mice were randomly assigned to the control group, and the exercise group, which were sacrificed immediately after an acute bout of exercise. The study was conducted to investigate the metabolic and transcriptional profiling in the quadriceps muscles of mice. The results demonstrated the identification of 34 differentially expressed metabolites (DEMs), with 28 upregulated and 6 downregulated, between the two groups. Metabolic pathway analysis revealed that these DEMs were primarily enriched in several, including the citrate cycle, propanoate metabolism, and lysine degradation pathways. In addition, the results showed a total of 245 differentially expressed genes (DEGs), with 155 genes upregulated and 90 genes downregulated. KEGG analysis indicated that these DEGs were mainly enriched in various pathways such as ubiquitin mediated proteolysis and FoxO signaling pathway. Furthermore, the analysis revealed significant enrichment of DEMs and DEGs in signaling pathways such as protein digestion and absorption, ferroptosis signaling pathway. In summary, the identified multiple metabolic pathways and signaling pathways were involved in the exercise-induced physiological regulation of skeletal muscle, such as the TCA cycle, oxidative phosphorylation, protein digestion and absorption, the FoxO signaling pathway, ubiquitin mediated proteolysis, ferroptosis signaling pathway, and the upregulation of KLF-15, FoxO1, MAFbx, and MuRF1 expression could play a critical role in enhancing skeletal muscle proteolysis.

The Warburg effect drives cachectic states in patients with pancreatobiliary adenocarcinoma.

We have studied whether the Warburg effect (uncontrolled glycolysis) in pancreatobiliary adenocarcinoma triggers cachexia in the patient. After 74 pancreatobiliary adenocarcinomas were removed by surgery, their glucose transporter-1 and four glycolytic enzymes were quantified using Western blotting. Based on the resulting data, the adenocarcinomas were equally divided into a group of low glycolysis (LG) and a group of high glycolysis (HG). Energy homeostasis was assessed in these cancer patients and in 74 non-cancer controls, using serum albumin and C-reactive protein and morphometrical analysis of abdominal skeletal muscle and fat on computed tomography scans. Some removed adenocarcinomas were transplanted in nude mice to see their impacts on host energy homeostasis. Separately, nude mice carrying tumor grafts of MiaPaCa-2 pancreatic adenocarcinoma cells were treated with the glycolytic inhibitor 3-bromopyruvate and with emodin that inhibited glycolysis by decreasing hypoxia-inducible factor-1α. Adenocarcinomas in both group LG and group HG impaired energy homeostasis in the cancer patients, compared to the non-cancer reference. The impaired energy homeostasis induced by the adenocarcinomas in group HG was more pronounced than that by the adenocarcinomas in group LG. When original adenocarcinomas were grown in nude mice, their glycolytic abilities determined the levels of hepatic gluconeogenesis, skeletal muscle proteolysis, adipose-tissue lipolysis, and weight loss in the mice. When MiaPaCa-2 cells were grown as tumors in nude mice, 3-bromopyruvate and emodin decreased tumor-induced glycolysis and cachexia, with the best effects being seen when the drugs were administered in combination. In conclusion, the Warburg effect in pancreatobiliary adenocarcinoma triggers cancer cachexia.

Time Course of Proteolysis Biomarker Responses to Resistance, High-Intensity Interval, and Concurrent Exercise Bouts.

Godwin, JS, Telles, GD, Vechin, FC, Conceição, MS, Ugrinowitsch, C, Roberts, MD, and Libardi, CA. Time course of proteolysis biomarker responses to resistance, high-intensity interval, and concurrent exercise bouts. J Strength Cond Res 37(12): 2326-2332, 2023-Concurrent exercise (CE) combines resistance exercise (RE) and high-intensity interval exercise (HIIE) in the same training routine, eliciting hypertrophy, strength, and cardiovascular benefits over time. Some studies suggest that CE training may hamper muscle hypertrophy and strength adaptations compared with RE training alone. However, the underlying mechanisms related to protein breakdown are not well understood. The purpose of this study was to examine how a bout of RE, HIIE, or CE affected ubiquitin-proteasome and calpain activity and the expression of a few associated genes, markers of skeletal muscle proteolysis. Nine untrained male subjects completed 1 bout of RE (4 sets of 8-12 reps), HIIE (12 × 1 minute sprints at V̇ o2 peak minimum velocity), and CE (RE followed by HIIE), in a crossover design, separated by 1-week washout periods. Muscle biopsies were obtained from the vastus lateralis before (Pre), immediately post, 4 hours (4 hours), and 8 hours (8 hours) after exercise. FBXO32 mRNA expression increased immediately after exercise (main time effect; p < 0.05), and RE and CE presented significant overall values compared with HIIE ( p < 0.05). There was a marginal time effect for calpain-2 mRNA expression ( p < 0.05), with no differences between time points ( p > 0.05). No significant changes occurred in TRIM63/MuRF-1 and FOXO3 mRNA expression, or 20S proteasome or calpain activities ( p > 0.05). In conclusion, our findings suggest that 1 bout of CE does not promote greater changes in markers of skeletal muscle proteolysis compared with 1 bout of RE or HIIE.

Effects of branched-chain amino acid supplementation on skeletal muscle proteolytic pathways after exercise-induced muscle injury in rats

To explore the role of branched-chain amino acid(BCAA) supplementation on muscle damage and the regulation of Krüppel-like factor 15(KLF15) and nuclear factor kappa B(NF-κB) mediated proteolytic pathways after an acute eccentric exercise. Male SD rats were divided into placebo group(PLA) and BCAA group(BCAA) randomly, 32 rats per group. Both group were then placed into subgroups: placebo and pre-exercise group(PC), placebo and immediately after exercise group(PE), placebo and 6 h after exercise group(PE6), placebo and 12 h after exercise group(PE12), BCAA and pre-exercise group(BC), BCAA and immediately after exercise group(BE), BCAA and 6 h after exercise group(BE6), BCAA and 12 h after exercise group(BE12), 8 rats per group. Rats in BCAA groups were supplied with BCAA(1 g/(kg·d·BW), 3 days) before the exercise day and placebo groups with equal volume of distilled water. The exercised groups performed a 2 h eccentric exercise on treadmill(16 m/min, -16° slope). Blood and gastrocnemius were collected according to the time points. RT-qPCR was used to measure the mRNA expression of KLF15, NF-κB, FoxO1, Atrogin-1 and MuRF1 in gastrocnemius. (1) No damage was found in myocytes of BC and PC group. The process of morphological damage in BCAA group was relatively faster. (2) The mRNA expression levels of KLF15, FoXO1, Atrogin-1 and MuRF1 in PE were higher than those in PC(P&lt;0.05, P&lt;0.01), NF-κB and Atrogin-1 in PE12 were higher than those in PC(P&lt;0.05). The mRNA expression levels of FoXO1 in BE were higher than those in BC(P&lt;0.05). Compared with PE, the mRNA expression levels of KLF15, Atrogin-1 and MuRF1 in BE were lower(P&lt;0.05, P&lt;0.01), NF-κB and Atrogin-1 in BE12 were lower than those in PE12(P&lt;0.05). The level of serum 3-MH in PE12 group was higher than that in PC group(P&lt;0.05). The proteolysis of skeletal muscle after high-intensity eccentric exercise is mediated by two different pathways: KLF15 and NF-κB, whose activation is time-dependent. BCAA may reduce skeletal muscle proteolysis by lowering the level of gene transcription in the KLF15 and NF-κB related protein degradation pathway, which occurs immediately after exercise.

Effects of heat stress on markers of skeletal muscle proteolysis in dairy cattle

Heat stress (HS) markedly affects postabsorptive energetics and protein metabolism. Circulating urea nitrogen increases in multiple species during HS and it has been traditionally presumed to stem from increased skeletal muscle proteolysis; however, this has not been empirically established. We hypothesized HS would increase activation of the calpain and proteasome systems as well as increase degradation of autophagosomes in skeletal muscle. To test this hypothesis, lactating dairy cows (~139 d in milk; parity ~2.4) were exposed to thermal neutral (TN) or HS conditions for 7 d (8 cows/environment). To induce HS, cattle were fitted with electric blankets for the duration of the heating period and the semitendinosus was biopsied on d 7. Heat stress increased rectal temperature (1.3°C) and respiratory rate (38 breaths per minute) while it decreased dry matter intake (34%) and milk yield (32%). Plasma urea nitrogen (PUN) peaked following 3 d (46%) and milk urea nitrogen (MUN) peaked following 4 d of environmental treatment and while both decreased thereafter, PUN and MUN remained elevated compared with TN (PUN: 20%; MUN: 27%) on d 7 of HS. Contrary to expectations, calpain I and II abundance and activation and calpain activity were similar between groups. Likewise, relative protein abundance of E3 ligases, muscle atrophy F-box protein/atrogin-1 and muscle ring-finger protein-1, total ubiquitinated proteins, and proteasome activity were similar between environmental treatments. Finally, autophagosome degradation was also unaltered by HS. Counter to our hypothesis, these results suggest skeletal muscle proteolysis is not increased following 7 d of HS and call into question the presumed dogma that elevated skeletal muscle proteolysis, per se, drives increased AA mobilization.

Glucagon-like peptide-1 receptor agonist, semaglutide attenuates chronic liver disease-induced skeletal muscle atrophy in diabetic mice

A glucagon-like peptide-1 receptor agonist (GLP-1RA) has recently been established as a pharmacological option for the treatment of type 2 diabetes. Recent studies have demonstrated the molecular role of GLP-1R in skeletal muscle homeostasis; however, the therapeutic efficacy of semaglutide, a GLP-1RA, on skeletal muscle atrophy in chronic liver disease (CLD) under diabetic conditions remains unclear. In the present study, semaglutide effectively inhibited psoas muscle atrophy and suppressed declines in grip strength in a diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-fed diabetic KK-Ay mouse model. Moreover, semaglutide inhibited ubiquitin-proteosome-mediated skeletal muscle proteolysis and promoted myogenesis in palmitic acid (PA)-stimulated C2C12 murine myocytes. Mechanistically, this effect of semaglutide on skeletal muscle atrophy was mediated by multiple functional pathways. First, semaglutide protected against hepatic injury in mice accompanied by increased production of insulin-like growth factor 1 and reduced accumulation of reactive oxygen species (ROS). These effects were associated with decreased proinflammatory cytokines and ROS accumulation, leading to the suppression of ubiquitin-proteosome muscle degradation. Moreover, semaglutide inhibited the amino acid starvation-related stress signaling that was activated under chronic liver injury, resulting in the recovery of the mammalian target of rapamycin activity in the skeletal muscle of DDC-diet fed KK-Ay mice. Second, semaglutide improved skeletal muscle atrophy by directly stimulating GLP-1R in myocytes. Semaglutide induced cAMP-mediated activation of PKA and AKT, enhanced mitochondrial biogenesis, and reduced ROS accumulation, thereby resulting in inhibition of NF-κB/myostatin-mediated ubiquitin-proteosome degradation and the augmentation of heat-shock factor-1-mediated myogenesis. Collectively, semaglutide may have potential as a new therapeutic strategy for CLD-related skeletal muscle wasting.

Effects of cholecalciferol and calcitriol on skeletal muscle proteolysis in angiotensin II-induced atrophy in differentiated C2C12 cells

Vitamin D3 has been proposed as a potential treatment to improve muscle atrophy in sarcopenic patients. Several lines of evidence suggested a possible crosslink between vitamin D and renin-angiotensin system contributing to skeletal muscle atrophy in response to chronic diseases in aging population. Nevertheless, effects of vitamin D and its metabolite on skeletal muscle cells challenged with angiotensin II remain unclear. Therefore, the effects of cholecalciferol (VD3) and calcitriol (1,25VD3) on the ubiquitin-proteasome pathway in angiotensin II-induced skeletal muscle cell atrophy were investigated. Differentiated C2C12 skeletal muscle cells (myotubes) were used as in vitro study model. Myotubes were assigned into vehicle (veh), 1 μM angiotensin II (AII), 1 μM angiotensin II+100 nM cholecalciferol (AII+VD3), 1 μM angiotensin II+1 nM calcitriol (AII+1,25VD3) and 1 μM angiotensin II+10 μM losartan (AII+Lo) groups. Myotubes were applied with angiotensin II on day 4-6, while VD3 and 1,25VD3 were treated on day 5-6 of the differentiation phase. For AII+Lo group, losartan was administered at 2 h before angiotensin II at day 4 of the differentiation period. Cells were harvested at day 7 of differentiation phase for morphological and biochemical analyses. Angiotensin II resulted in significantly decreased myotube diameter and tended to increase protein expression of the transcription factor; FoxO3a and ubiquitin ligases; MURF-1 and atrogin-1, the major muscle protein catabolism pathway when compared with veh-treated group. Treatment of VD3 and losartan could protect angiotensin II-induced myotube atrophy. In contrast, 1,25VD3 accelerated muscle protein breakdown in myotube-challenged with angiotensin II. Protein expression of FoxO3a, MuRF1 and atrogin-1 was significantly up-regulated in AII+1,25VD3 group compared to veh, AII+VD3 and AII+Lo-treated groups. By which these occurs were accompanied with the overexpression of vitamin D receptor in myotube co-treated with angiotensin II and 1,25VD3. Herein, differential effects of VD3 and 1,25VD3 in angiotensin II-induced myotube atrophy were demonstrated. Administration of VD3 resulted in attenuated degree of muscle loss-induced by angiotensin II, while 1,25VD3 possessed the negative impact to skeletal muscle protein metabolism. Collectively, vitamin D3 supplement may be considered as an alternative adjuvant to alleviate muscle atrophy in the patients related to high level of angiotensin II. This work was financially supported by Office of the Permanent Secretary, Ministry of Higher Education, Science, Research and Innovation (Grant No. RGNS 63-216 to M.H.) and Srinakharinwirot University (to M.H.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

EXT418, a novel long-acting ghrelin, mitigates Lewis lung carcinoma induced cachexia in mice.

Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half-life of active (acylated) ghrelin (~11min in humans). EXT418 is a novel long-acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)-induced cachexia in mice. Male C57BL/6J mice (5- to 7-month-old) were implanted with 1×106 heat-killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T+V) or EXT418 daily (T+418 Daily, 0.25mg/kg/day) or every other day (T+418 EOD, 0.5mg/kg/EOD) for up to 14days, whereas HK-treated mice were given vehicle (HK+V). Subsets of T+418 Daily or EOD-treated mice were pair-fed to the T+V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination. In tumour-bearing mice, administration of EXT418 daily or EOD partially prevented weight loss (T+V vs. T+418 Daily, P=0.030; and vs. T+418 EOD, P=0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour-bearing mice was improved by EXT418 daily (P=0.010) or EOD (P=0.008) administration compared with vehicle-treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. EXT418 daily administration also improved type IIA (P=0.015), IIB (P=0.037) and IIX (P=0.050) fibre cross-sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P=0.005). In skeletal muscles, tumour-induced increases in atrogenes Fbxo32 and Trim63 were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker Bnip3 (GAS/PL; P≤0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P=0.039). In addition, EXT418 treatments ameliorated the tumour-induced elevation in muscle Il6 transcript levels (TA and GAS/PL), independently of food intake. Il-6 transcript levels in adipose tissue and circulating IL-10 were elevated in response to the tumour but these increases were not significant with EXT418 administration. Tumour mass was not altered by EXT418. EXT418 mitigates LLC-induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake.

Metabolomics reveals that alcohol extract of propolis alleviates D-gal-induced skeletal muscle senescence in mice

Propolis is an important functional food with numerous biological properties, such as anti-oxidation, anti-inflammation, and immune regulation. However, there are few studies on the effects of propolis on aging-induced muscle atrophy. Here, we aimed to determine whether propolis exerts protective effects against muscle damage caused by d-galactose (D-gal)-induced aging in mice. Propolis was found to ameliorate the morphological alterations generated by D-gal in muscle fibers and considerably increase their cross-sectional area and diameter; ameliorate muscle oxidative stress by boosting Nrf2 and HO-1 expression and Nrf2 nuclear translocation; reduce apoptosis in muscle cells by dramatically increasing Bcl2 expression and decreasing Bax expression; and significantly decreased the level of MAFbx and MuRF1, thus inhibiting skeletal muscle proteolysis. Metabonomic studies showed that propolis can promote protein metabolism and reduce oxidative stress in skeletal muscle. Propolis may reduce prostaglandin and estriol levels by increasing the blood supply to aging skeletal muscles and reducing the lipid peroxide tablets. Propolis may inhibit skeletal muscle cell apoptosis by suppressing isoprenaline metabolism in skeletal muscle, thus playing a role in anti-skeletal muscle aging. Propolis delays skeletal muscle aging by reducing oxidative stress, inhibiting apoptosis, and regulating muscle protein metabolism.

Atrogin-1 knockdown inhibits the autophagy-lysosome system in mammalian and avian myotubes

Atrogin-1 plays an important role in ubiquitin-proteasome proteolysis in vertebrate skeletal muscles. Recently, atrogin-1 has been shown to be involved in the autophagy-lysosome system, another proteolytic system, in the murine and fish hearts and skeletal muscles. With the aim to elucidate the effect of atrogin-1 on the autophagy-lysosome system in mammalian and avian skeletal muscles, this study has examined the effects of atrogin-1 knockdown on autophagy-lysosome-related proteins in C2C12 and chicken embryonic myotubes. Using the levels of microtubule-associated protein light chain 3 (LC3)-II protein, it was confirmed that atrogin-1 knockdown blocked the autophagic flux in both the myotubes. In addition, atrogin-1 knockdown in C2C12 myotubes significantly decreased the level of autophagy-related gene (ATG)12-ATG5 conjugate, which is supposedly necessary for the fusion of autophagosomes and lysosomes. Atrogin-1 knockdown also resulted in downregulation of forkhead box O3, a transcription factor for ATG12. These data suggest that atrogin-1 is essential for the normal autophagy-lysosome system in the striated muscles of vertebrates.

Dynamics and Interplay between Autophagy and Ubiquitin-proteasome system Coordination in Skeletal Muscle Atrophy.

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.

Hyperbaric Oxygen Therapy Following Cervical Spinal Cord Injury Increases BDNF/TrkB Signaling in Diaphragm Muscle

Respiratory insufficiency is the leading cause of morbidity and mortality following cervical spinal cord injury (SCI). Diaphragm atrophy following SCI occurs as a result of damage to respiratory neural circuitry, which leads to impaired muscle contractility. Disruption of redox balance occurs after SCI and increased mitochondrial reactive oxygen species production is an upstream trigger for diaphragm muscle atrophy and weakness. Recently, we demonstrated that increased antioxidant capacity in response to hyperbaric oxygen (HBO) therapy may play a role in preserving mitochondrial redox homeostasis following SCI. However, a precise understanding of the mechanisms by which HBO therapy can prevent diaphragm dysfunction is lacking. In this regard, evidence indicates that the secretion of neurotrophic factors, such as brain derived neurotrophic factor (BDNF), may also contribute to enhanced functional recovery when HBO therapy is initiated acutely following cervical SCI. Through activation of the 5′ adenosine monophosphate‐activated protein kinase (AMPK) and serine‐threonine protein kinase (AKT) signaling via the phosphorylation of its receptor tropomyosin receptor kinase B (TrKb), BDNF expression has been shown to modulate mitochondrial biogenesis and skeletal muscle proteolysis. Therefore, we tested the hypothesis that 10 days of HBO therapy initiated in the acute phase following cervical SCI can increase diaphragm mitochondrial biogenesis and prevent diaphragm proteolytic signaling by activating BDNF/TrkB signaling. To test this, adult male Sprague‐Dawley rats were separated into three groups (n=8/group): (1) non‐injured, room air exposure (CON); (2) lateral‐cervical spinal cord contusion, room air exposure (SCI); and (3) lateral‐cervical spinal cord contusion, HBO therapy (SCI+HBO). Animals in the SCI and SCI+HBO groups were anesthetized, and following laminectomy at the C3–C4 level, a lateral‐cervical spinal contusion was made using a mechanical impactor. HBO therapy consisted of 10 days of exposure starting on the day of SCI, using a 40 L chamber flushed with 100% O2 and pressurized to 3 ATA. Our results indicate that HBO therapy delivered in the acute phase of SCI positively affected BDNF/TrkB signaling. Specifically, diaphragm protein expression of BDNF, p‐AKT/AKT and p‐AMPK/AMPK were increased after 10 days of HBO therapy compared to CON animals (p&lt;0.05). Additionally, HBO therapy prevented the SCI‐induced reduction in diaphragm peroxisome proliferator‐activated receptor‐gamma coactivator (PGC1‐α) protein expression (p&lt;0.05), as well as the caspase‐3‐specific cleavage of α‐II‐spectrin observed in the SCI group (p&lt;0.05). In summary, these findings demonstrate that HBO therapy can induce BDNF signaling and highlight an additional mechanism for the protective effects of HBO therapy to preserve diaphragm muscle function following SCI.

Evaluation of Anti-diabetic Activity of Bambusa Bambos using Streptozocin Diabetic Model Induced

Diabetes mellitus, commonly known as diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. If left untreated, diabetes can cause many health complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes and cognitive impairment. Herbal medicine is a drug or preparation made from plants or parts of plant (leaves, root, bark, seeds and flowers) valued for its medicinal, aromatic or savoury qualities to treat the symptoms of wide range of problems from depression to cold and flu. Herbal medicine has been widely used for thousands of years. One of them is Bambusa bambos which is very well known for its ethno pharmacological activities, also known as Bans in hindi andvansa in sanskrit. leaves were washed and dried was extracted with hydroalcohol. The present study represents the assessment of anti- hyperglycemic effects of the hydro alcoholic extract from bambusa bambos in streptozotocin (STZ) induced diabetic rats. The bambusa bambos hydoalcoholic extracts at the tested doses of 100, 200 and 400 mg/kg showed comparable activity with the standard. Metformin decreases hyperglycaemia primarily by suppressing glucose production by the liver. The streptozotocin induced diabetes is characterized by a severe loss in body weight. The decrease in the body weight of diabetic rats in this study was due to the loss or degradation of structural proteins. Insulin plays an important role in the regulation of protein synthesis and proteolysis in skeletal muscle. In the present study, diabetic control rats showed marked reduction in their body weight when compared to normal rats. The ability of the extract to protect body weight loss in diabetic rats seems to be the result of their ability to reduce hyperglycemia. During the study, it was found that the extract significantly (p&lt;0.001) controlled the blood glucose level in STZ-induced diabetic rats. The bambusa bambos hydroalcoholic extracts showed reduction in blood glucose level in STZ-induced diabetic rats when compared to the diabetic control group at a dose of 400 mg/kg,&#x0D; Keywords: Bambusa bambos, Hydroalcoholic extracts, Metformin, Streptozotocin.

Cancer-cell-secreted miR-122 suppresses O-GlcNAcylation to promote skeletal muscle proteolysis.

A decline in skeletal muscle mass and lower muscular strength are prognostic factors in advanced human cancers. Here, we found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in muscle through extracellular-vesicle-encapsulated miR-122, which targets O-GlcNAc transferase (OGT). Mechanistically, O-GlcNAcylation of the ryanodine receptor 1 (RYR1) competed with NEK10-mediated phosphorylation and increased K48-linked ubiquitination and proteasomal degradation; the miR-122-mediated decrease in OGT resulted in increased RYR1 abundance. We further found that muscular protein O-GlcNAcylation was regulated by hypoxia and lactate through HIF1A-dependent OGT promoter activation and was elevated after exercise. Suppressed O-GlcNAcylation in the setting of cancer, through increasing RYR1, led to higher cytosolic Ca2+ and calpain protease activation, which triggered cleavage of desmin filaments and myofibrillar destruction. This was associated with reduced skeletal muscle mass and contractility in tumour-bearing mice. Our findings link O-GlcNAcylation to muscular protein homeostasis and contractility and reveal a mechanism of cancer-associated muscle dysregulation.

Bcaa Alleviates Rats Skeletal Muscle Protein Degradation After Eccentric Exercise By Reducing KLF15 Expression

PURPOSE: Exercise-induced muscle damage after high-intensity eccentric exercise can lead to degradation of skeletal muscle protein, thereby affecting the training effect. The purpose of this study is to explore the effect of branched-chain amino acid (BCAA) supplementation on muscle damage caused by one-time eccentric exercise, and the regulation of KLF15-mediated proteolytic pathways in the process. METHODS: 64 male SD rats were randomly divided into eight groups: placebo + control group (PC, n = 8), placebo + immediately after exercise group (PE, n = 8), placebo +6 h after exercise group (PE6, n = 8), placebo +12 h after exercise group (PE12, n = 8), BCAA + control group (BC, n = 8), BCAA + immediately after exercise group (BE, n = 8), BCAA +6 h after exercise group (BE6, n = 8), BCAA +12 h after exercise group (BE12, n = 8). Rats in BCAA groups were supplied BCAA (1 g/kg/day) 3 times before exercise. The placebo groups were supplied the same volume of distilled water. Rats in exercise groups underwent a bout of 2 h eccentric exercise on treadmill (-16° slope, a speed of 16 m/min). Blood and gastrocnemius were collected immediately after exercise in PE and BE, 6 h after exercise in PE6 and BE6, and 12 h after exercise in PE12 and BE12. The expression of 3-MH in blood was detected by ELISA. RT-qPCR was used to measure the mRNA expression of KLF15, Atrogin-1, MuRF-1 and MHC-II in gastrocnemius. RESULTS: The mRNA expression of MHC-II (P < 0.05), KLF15 (P < 0.05), Atrogin-1 (P < 0.05), MuRF-1 (P < 0.01) in PE were higher than those in PC, MHC-II (P < 0.05) in PE6 and Atrogin-1 (P < 0.05) in PE12 were higher than in PC. MHC-II (P < 0.05) was higher in BE6 than in BE. Compared with PE, the mRNA expression of KLF15 (P < 0.01), Atrogin-1(P < 0.05), MuRF-1 (P < 0.01) in BE were significantly lower, Atrogin-1 (P < 0.05) in BE12 was lower than that in PE12. 3-MH (P < 0.05) content was higher in PE12 than in PC, 3-MH (P < 0.01) content was lower in BE and BE6 than in BC, 3-MH (P < 0.01) content was higher in BC than in PC. CONCLUSIONS: BCAA may reduce skeletal muscle proteolysis by lowering the level of gene transcription in the KLF15-related protein degradation pathway, which occurs immediately after exercise.

Caveolin‐1 increases glycolysis in pancreatic cancer cells and triggers cachectic states

In pancreatic cancer, autocrine insulin-like growth factor-1 (IGF-1) and paracrine insulin stimulate both IGF-1 receptor (IGF1R) and insulin receptor (IR) to increase tumor growth and glycolysis. In pancreatic cancer patients, cancer-induced glycolysis increases hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis and, thereby, causes cancer cachexia. As a protein coexisting with IGF1R and IR, caveolin-1 (cav-1) may be involved in pancreatic cancer-induced cachexia. We undertook the present study to test this hypothesis. Out of wild-type MiaPaCa2 and AsPC1 human pancreatic cancer cell lines, we created their stable sub-lines whose cav-1 expression was diminished with RNA interference or increased with transgene expression. When these cells were studied in vitro, we found that cav-1 regulated IGF1R/IR expression and activation and also regulated cellular glycolysis. We transplanted the different types of MiaPaCa2 cells in growing athymic mice for 8 weeks, using intact athymic mice as tumor-free controls. We found that cav-1 levels in tumor grafts were correlated with expression levels of the enzymes that regulated hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis in the respective tissues. When the tumors had original or increased cav-1, their carriers’ body weight gain was less than the tumor-free reference. When cav-1 was diminished in tumors, the tumor carriers’ body weight gain was not changed significantly, compared to the tumor-free reference. In conclusion, cav-1 in pancreatic cancer cells stimulated IGF1R/IR and glycolysis in the cancer cells and triggered cachectic states in the tumor carrier.