Search Results (39)

Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues. Full article

Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the progressive loss of motor neurons and consequent muscle atrophy. Although SMN-targeted therapies have significantly improved survival and motor outcomes, residual muscle weakness remains a major clinical challenge, particularly in patients treated later in the disease course. Myostatin, a potent negative regulator of skeletal muscle mass, has emerged as a promising therapeutic target to address this gap. This review summarizes the preclinical and clinical evidence supporting the modulation of the myostatin pathway in SMA. Preclinical studies have demonstrated that inhibiting myostatin, especially when combined with SMN-enhancing agents, can increase muscle mass, improve motor function, and enhance neuromuscular connectivity in SMA mouse models. These findings provide a strong rationale for translating myostatin inhibition into clinical practice as an adjunctive strategy. Early clinical trials investigating myostatin inhibitors have shown favorable safety profiles and preliminary signs of target engagement. However, large-scale trials have yet to demonstrate widespread, robust efficacy across diverse patient populations. Despite this, myostatin pathway inhibition remains a compelling approach, particularly when integrated into broader treatment paradigms aimed at enhancing motor unit stability and function in individuals with SMA. Further clinical research is essential to validate efficacy, determine optimal timing, and define the patient subgroups most likely to benefit from myostatin-targeted therapies. Full article

Diabetic muscular atrophy is a complication of diabetes mellitus that can decrease quality of life. Its complex mechanisms include alterations in proteolytic pathways, oxidative stress, and intracellular lipid accumulation. NADPH oxidase enzymes (NOX) play a key role in the production of ROS, contributing to oxidative damage and insulin resistance. Apocynin, a NOX inhibitor, has antioxidant and anti-inflammatory effects, suggesting its therapeutic potential in various diabetic complications. This study evaluated the impact of apocynin on the mechanisms of muscle atrophy in slow- and fast-twitch muscles of diabetic rats. Diabetes was induced in male Wistar rats by intraperitoneal injection of a single dose of streptozotocin (60 mg/kg). Apocynin treatment (3 mg/kg/day) was administered for 8 weeks. Fasting blood glucose levels, lipid profile, and weight gain were measured. Both slow-twitch (soleus) and fast-twitch (extensor digitorum longus, EDL) skeletal muscles were weighed and used to assess triglycerides (TG) content, histological analysis, lipid peroxidation levels, and gene expression evaluated by qRT-PCR. Apocynin reduced blood glucose levels, improved body weight, and exhibited hypolipidemic effects. It significantly increased muscle weight in EDL and soleus, especially in EDL muscle, lowering triglycerides, lipid peroxidation, and increasing fiber size. Additionally, it decreased mRNA expression levels of MuRF-1, atrogin-1, myostatin and p47phox mRNA and upregulated PGC-1α and follistatin mRNA. Apocynin exerted a myoprotective effect by mitigating muscle atrophy in diabetic rats. Its effects were differentially mediated on TG accumulation and muscle fiber size, reducing oxidative stress, atrogene expression, and positively regulating PGC-1α. Full article

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors continually stabilize hypoxia-inducible factor-1α (HIF-1α). These inhibitors are effective in the clinical treatment of renal anemia. However, the effects of continued HIF-1α stabilization on skeletal muscle differentiation remain unclear. This study aimed to investigate the effects of continued HIF-1α stabilization on skeletal muscle differentiation using a HIF-PH inhibitor in both in vitro and in vivo models. We cultured mouse C2C12 myoblasts to differentiate into myotubes with or without FG-4592, a HIF-PH inhibitor. Additionally, we treated nine-week-old male C57BL/6 mice with either FG-4592 or vehicle via intraperitoneal injections three times a week for four weeks. In vitro, FG-4592 treatment stabilized HIF-1α continually. Morphological analysis revealed that 72 h FG-4592 treatment suppressed differentiation of C2C12 myoblasts into myotubes. This treatment decreased the gene and protein expression of MyoD and myogenin, reduced the protein expression of myosin heavy chain (MHC), and increased the gene and protein expression of myostatin. HIF-1α knockdown mitigated the decrease in MHC protein expression induced by FG-4592. In vivo, FG-4592 treatment increased HIF-1α protein expression and decreased MyoD, myogenin, and MHC protein expression in gastrocnemius muscle. These findings suggest that pharmacological HIF-PH inhibition suppresses myoblast differentiation through continued HIF-1α stabilization. Full article

Sarcopenic obesity (SO), characterized by an excess of fat and a decrease in muscle strength or mass, is a global public health concern and is linked to metabolic conditions such as metabolic syndrome (MetS). Different mechanisms contribute to SO, such as inflammation, fatty acid infiltration, and insulin resistance (IR). Recently, myostatin (MYOST), an inhibitory factor for skeletal muscle tissue, was proposed as an aimed compound for the treatment of conditions of muscular metabolic imbalance mass and MetS. On the other hand, a therapy with natural compounds such as resveratrol (R) and quercetin (Q) is effective for the treatment of MetS, but its effect on the MYOST pathway has been poorly explored. The control group received water, and the MetS group received 30% commercial sugar in the drinking water for 6 months. Polyphenol mix (R at a dose of 50 mg/kg/day and Q at 0.95 mg/kg/day) was administered for 1 month. MetS rats present SO linked to an increase in the expression of MYOST/ActRIIA and ActRIIB (p < 0.0001). R+Q treatment prevented SO by lowering the expression of MYOST and its receptors and increased the expression of Smad 7 in MetS rats (p < 0.0001). Moreover, the polyphenol treatment reverted IR by increasing Akt phosphorylation, leading to an increase in muscle mass. It decreased lipid stores, restored glycogen accumulation, and increased myosin expression (p < 0.0001). The results of this work indicate that R+Q supplementation could be a promising therapeutic agent to prevent SO and sarcopenia derived from other metabolic alterations. Full article

Sarcopenia, a serious consequence of chronic kidney disease (CKD), is driven by elevated myostatin (MSTN), a key inhibitor of muscle growth. This study explored the potential of an MSTN-specific antisense oligonucleotide (ASO) in reversing CKD-induced muscle wasting in a mouse model. Thirty-two male C57BL/6J mice were randomly assigned to a non-CKD group (n = 8, regular diet) and a CKD group (n = 24, adenine diet). CKD was induced using a 0.2% adenine-supplemented diet for 4 weeks. Following this, the mice were sub-grouped into CKD (saline, n = 8), CKD + Low-Dose ASO (25 mg/kg ASO, n = 8), and CKD + High-Dose ASO (50 mg/kg ASO, n = 8). ASO was administered via subcutaneous injections for 8 weeks. Muscle mass, treadmill performance, grip strength, and muscle fiber morphology were assessed alongside qPCR and Western blot analysis for MSTN, atrogin-1, and MuRF-1 expression. ASO therapy significantly enhanced muscle mass and function and enlarged muscle fibers while effectively downregulating muscle degradation markers. These improvements occurred without compromising renal function, as confirmed by BUN, creatinine, kidney weight, and histological analysis. This study is the first to demonstrate the efficacy of ASO therapy in mitigating CKD-induced sarcopenia, offering a promising targeted gene therapy with significant clinical implications for improving nutritional status and physical performance in CKD. Full article

Chronic kidney disease (CKD) is a progressive condition linked to sarcopenia, a syndrome characterized by loss of skeletal muscle mass and strength, affecting a quarter of CKD patients globally. Sarcopenia has multiple paths through which it can worsen morbidity and mortality as well as decrease the quality of life in CKD, including systemic inflammation, hormonal imbalances, metabolic changes, and dysbiosis of gut microbiota. There is a regional variation in the criteria set for diagnosis, with two main groups being the European Working Group on Sarcopenia in Older People and the Asian Working Group for Sarcopenia. Management regimes such as nutritional optimization, vitamin D, exercise, correction of metabolic acidosis, and modulation of gut microbiota constitute effective intervention strategies. Emerging therapeutic options include anabolic agents, myostatin inhibitors, and anti-inflammatory treatment options. Future advances such as genomics, proteomics, and personalized medicine will open up new avenues for addressing the complex pathophysiology of sarcopenia. Hence, a comprehensive multidisciplinary approach focused on the specific needs of each patient will be vital in reducing the effects of sarcopenia and improving the situation of people with CKD. Full article

Cultured meat (CM) is derived from the in vitro myogenesis of muscle satellite (stem) cells (MSCs) and offers a promising alternative protein source. However, the development of a cost-effective media formulation that promotes cell growth has yet to be achieved. In this study, laxogenin (LAX) and 5-alpha-hydroxy-laxogenin (5HLAX) were computationally screened against myostatin (MSTN), a negative regulator of muscle mass, because of their antioxidant properties and dual roles as MSTN inhibitors and enhancers of myogenesis regulatory factors. In silico analysis showed LXG and 5HLXG bound to MSTN with binding free energies of −7.90 and −8.50 kcal/mol, respectively. At a concentration of 10 nM, LAX and 5HLAX effectively inhibited the mRNA and protein expressions of MSTN, promoted myogenesis, and enhanced myotube formation and maturation. In addition, by acting as agonists of ROS downregulating factors, they exhibited antioxidative effects. This study shows that supplementation with LAX or 5HLAX at 10 nM in CM production improves texture, quality, and nutritional value. We believe this study fills a research gap on media development for myotube formation and maturation, which are important factors for large-scale in vitro CM production that improve product quality, nutritional value, and efficacy. Full article

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA. Full article

Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels’ correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients’ age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials. Full article

Metabolic syndrome prevalence is between 24 and 27% and poses a significant risk for the development of atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes (T2D), or other comorbidities. Currently, no drugs are approved for metabolic syndrome treatment itself, so the risk factors are treated with therapies approved for cardiac and metabolic conditions. These are approved drugs for dyslipidemia treatment such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, cornerstone antihypertensive drugs, or novel class glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) for T2D and overweight or obesity treatment. We have also evaluated new pharmacological interventions in clinical development that have reached Phase 2 and/or Phase 3 randomized clinical trials (RCTs) for the management of the risk factors of metabolic syndrome. In the pipeline are glucose-dependent insulinotropic polypeptide (GIP), GLP-1, glucagon receptor (GCGR), amylin agonists, and a combination of the latter for T2D and overweight or obesity treatment. Non-entero-pancreatic hormone-based therapies such as ketohexokinase (KHK) inhibitor, growth differentiation factor 15 (GDF15) agonists, monoclonal antibodies (mAbs) as activin type II receptors (ActRII) inhibitors, and a combination of anti-α-myostatin (GFD8) and anti-Activin-A (Act-A) mAbs have also reached Phase 2 or 3 RCTs in the same indications. Rilparencel (Renal Autologous Cell Therapy) is being evaluated in patients with T2D and chronic kidney disease (CKD) in a Phase 3 trial. For dyslipidemia treatment, novel PCSK9 inhibitors (oral and subcutaneous) and cholesteryl ester transfer protein (CETP) inhibitors are in the final stages of clinical development. There is also a surge of a new generation of an antisense oligonucleotide (ASO) and small interfering RNA (siRNA)-targeting lipoprotein(a) [Lp(a)] synthesis pathway that could possibly contribute to a further step forward in the treatment of dyslipidemia. For resistant and uncontrolled hypertension, aldosterone synthase inhibitors and siRNAs targeting angiotensinogen (AGT) messenger RNA (mRNA) are promising new therapeutic options. It would be interesting if a few drugs in clinical development for metabolic syndrome such as 6-bromotryptophan (6-BT), vericiguat, and INV-202 as a peripherally-acting CB1 receptor (CB1r) blocker would succeed in finally gaining the first drug approval for metabolic syndrome itself. Full article

Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1β. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines. Full article

Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment. Full article

Cancer cachexia is a multifactorial syndrome that interferes with treatment and reduces the quality of life and survival of patients. Currently, there is no effective treatment or biomarkers, and pathophysiology is not clear. Our group reported alterations on tryptophan metabolites in cachectic patients, so we aim to investigate the role of tryptophan using two cancer-associated cachexia syngeneic murine models, melanoma B16F10, and pancreatic adenocarcinoma that is KPC-based. Injected mice showed signs of cancer-associated cachexia as reduction in body weight and raised spleen weight, MCP1, and carbonilated proteins in plasma. CRP and Myostatin also increased in B16F10 mice. Skeletal muscle showed a decrease in quadriceps weight and cross-sectional area (especially in B16F10). Higher expression of atrophy genes, mainly Atrogin1, was also observed. Plasmatic tryptophan levels in B16F10 tumor-bearing mice decreased even at early steps of tumorigenesis. In KPC-injected mice, tryptophan fluctuated but were also reduced and in cachectic patients were significantly lower. Treatment with 1-methyl-tryptophan, an inhibitor of tryptophan degradation, in the murine models resulted in the restoration of plasmatic tryptophan levels and an improvement on splenomegaly and carbonilated proteins levels, while changes in plasmatic inflammatory markers were mild. After the treatment, CCR2 expression in monocytes diminished and lymphocytes, Tregs, and CD8+, were activated (seen by increased in CD127 and CD25 expression, respectively). These immune cell changes pointed to an improvement in systemic inflammation. While treatment with 1-MT did not show benefits in terms of muscle wasting and atrophy in our experimental setting, muscle functionality was not affected and central nuclei fibers appeared, being a feature of regeneration. Therefore, tryptophan metabolism pathway is a promising target for inflammation modulation in cancer-associated cachexia. Full article

Myostatin, an important negative regulator of muscle mass, is a therapeutic target for muscle atrophic disorders such as muscular dystrophy. Thus, the inhibition of myostatin presents a strategy to treat these disorders. It has long been established that the myostatin prodomain is a strong inhibitor of the mature myostatin, and the minimum peptide of the prodomain—corresponding to the α₁-helix of its lasso-region—responsible for the inhibitory efficiency was defined and characterized as well. Here we show that the minimum peptide segment based on the growth differentiation factor 11 (GDF11), which we found to be more helical in its stand-alone solvated stfate than the similar segment of myostatin, is a promising new base scaffold for inhibitor design. The proposed inhibitory peptides in their solvated state and in complex with the mature myostatin were analyzed by in silico molecule modeling supplemented with the electronic circular dichroism spectroscopy measurements. We defined the Gaussian–Mahalanobis mean score to measure the fraction of dihedral angle-pairs close to the desired helical region of the Ramachandran-plot, carried out RING analysis of the peptide-protein interaction networks and characterized the internal motions of the complexes using our rigid-body segmentation protocol. We identified a variant—11m2—that is sufficiently ordered both in solvent and within the inhibitory complex, forms a high number of contacts with the binding-pocket and induces such changes in its internal dynamics that lead to a rigidified, permanently locked conformation that traps this peptide in the binding site. We also showed that the naturally evolved α₁-helix has been optimized to simultaneously fulfill two very different roles: to function as a strong binder as well as a good leaving group. It forms an outstanding number of non-covalent interactions with the mature core of myostatin and maintains the most ordered conformation within the complex, while it induces independent movement of the gate-keeper β-hairpin segment assisting the dissociation and also results in the least-ordered solvated form which provides extra stability for the dissociated state and discourages rebinding. Full article