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Aim: To explore the effects and mechanisms of different concentrations of uric acid on skeletal muscle cells., Methods: C2C12 myoblasts were differentiated into myotubes and then exposed to a medium containing uric acid (0 μM, 200 μM, 400 μM, 600 μM, 800 μM, 1000 μM, 1200 μM, 1400 μM). The myotube diameters were observed under light microscopy; the expressions of myosin heavy chain (MyHC), autophagy-related proteins (LC3BII/LC3BI, P62), cGAS, and p-Sting/Sting proteins were analyzed using Western blotting or immunoprecipitation; and oxidative stress and mitochondrial damage were evaluated using ROS, mtDNA and JC-1 assays. Cell viability was measured via CCK8 assay, and 1000-μM uric acid was selected for follow-up experiments. Furthermore, C2C12 myotubes were divided into a blank control group (Ctrl), a high-uric-acid group (HUA), and an HUA plus cGASn inhibitor group (HUA + RU.521). Then, the myotube diameter was observed, oxidative stress and mitochondrial damage were evaluated, and MyHC and autophagy-related protein expressions were analysed., Results: C2C12 myotubes cultured in 400-μM uric acid medium had the greatest myotube diameter and the highest MyHC protein expression. At 1000-μM uric acid, the diameter and MyHC protein expression were significantly decreased, LCB3II/LCB3I expression was notably increased, and the level of p62 protein expression was considerably decreased. RU.521 partially alleviated the HUA-induced C2C12 myotubes changes., Conclusions: Uric acid bidirectionally affected C2C12 myotubes: 400-μΜ uric acid promoted myotube growth, while 1000-μΜ uric acid triggered myotube atrophy with increased autophagy. Inhibiting cGAS-Sting signaling attenuated HUA-induced C2C12 myotube autophagy and atrophy. Geriatr Gerontol Int 2024; 24: 430-439., (© 2024 Japan Geriatrics Society.)

There is limited experimental evidence on the biochemical consequences of aluminium (Al) and cadmium (Cd) co-exposures during pregnancy and postnatal life.This study investigated the impacts of perinatal Al chloride (AlCl 3 ) and Cd chloride (CdCl 2 ) co-exposures on neuroendocrine functions in mice offspring during postnatal life. The study comprised of four pregnant experimental groups. Group 1 received AlCl 3 (10 mg/kg), group 2 were administered CdCl 2 (1.5 mg/kg), while group 3 received both AlCl 3 (10 mg/kg) and CdCl 2 (1.5 mg/kg) (AlCl 3 +CdCl 2 ), and group 4 received saline (10 mL/kg) only and served as control group. All experimental animals were chemically exposed once daily from gestation days 7-20. Upon delivery, male pups were regrouped based on maternal chemical exposure on postnatal day 21 (PND 21) and allowed to grow to adulthood until PND 78, after which they were sacrificed for assessment of neuroendocrine markers and histological investigations. There was no statistical significance (p > 0.05) on follicle stimulating hormone, testosterone, estrogen and progesterone, thyroid stimulating hormone, thyroxine (T4) in all treatment groups relative to controls|. However, AlCl 3 and AlCl 3 -CdCl 2 significantly (p < 0.05) reduced triiodothyronine (T3) levels, with a profound increase in T3:T4 ratio by AlCl 3 , and AlCl 3 +CdCl 2 compared to control. Furthermore, pups from pregnant mice treated with CdCl 2 and AlCl 3 +CdCl 2 demonstrated increased testicular malondialdehyde concentration with increased catalase activity relative to controls, suggesting oxidative imbalance. In addition, AlCl 3 , CdCl 2 , and AlCl 3 +CdCl 2 exposures induced testicular and hypothalamic architectural disruption compared to controls, with marked architectural derangement in the AlCl 3 +CdCl 2 group. Our findings suggest that prenatal co-exposures to Alcl 3 and CdCl 2 induce testicular and hypothalamic alterations in offspring via a testicular oxidative stress and thyrotoxicosis-dependent mechanisms., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analog, ALY688-SR, remodels the diaphragm of murine model of DMD on DBA background (D2. mdx ) mice treated from days 7-28 of age during early stages of disease. ALY688-SR also lowered interleukin-6 (IL-6) mRNA but increased IL-6 and transforming growth factor-β1 (TGF-β1) protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H 2 O 2 emission. Treatment also attenuated fibrosis, fiber type-specific atrophy, and in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling, and force-generating properties during the very early stages of disease progression in murine model of DMD on DBA background (D2. mdx ) mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR in young D2. mdx mice partially prevents fibrosis and fiber type-specific atrophy and lowers force production in the more disease-apparent diaphragm in relation to lower mitochondrial redox stress and heterogeneous responses in certain inflammatory markers. These diverse muscle responses to adiponectin receptor agonism in early stages of DMD serve as a foundation for further mechanistic investigations. NEW & NOTEWORTHY There are limited therapies for the treatment of Duchenne muscular dystrophy. As fibrosis involves an accumulation of collagen that replaces muscle fibers, antifibrotics may help preserve muscle function. We report that the novel adiponectin receptor agonist ALY688-SR prevents fibrosis in the diaphragm of D2. mdx mice with short-term treatment early in disease progression. These responses were related to altered inflammation and mitochondrial functions and serve as a foundation for the development of this class of therapy.

Background: Fat infiltration in muscle, called 'myosteatosis', precedes muscle atrophy, which subsequently results in sarcopenia. Myosteatosis is frequently observed in patients with nonalcoholic fatty liver disease (NAFLD). We have previously reported that retinoic acid receptor-related orphan receptor-α (RORα) regulates mitochondrial dynamics and mitophagy in hepatocytes, resulting in an alleviation of NAFLD. In this study, we aimed to investigate the role of RORα in skeletal muscle and to understand molecular mechanisms by which RORα controls mitochondrial capacity, using an NAFLD-associated myosteatosis mouse model., Methods: To establish a myosteatosis model, 7-week-old C57BL/6N mice were fed with high-fat diet (HFD). After 15 weeks of diet feeding, an adeno-associated virus vector encoding RORα (AAV-RORα) was injected to gastrocnemius (GA) muscles, or after 7 weeks of HFD feeding, JC1-40, an RORα agonistic ligand, was administered daily at a dose of 5 mg/kg/day by oral gavage for 5 weeks. Histological, biochemical and molecular analyses in various in vivo and in vitro experiments were performed., Results: First, the number of oxidative MyHC2a fibres with intensive lipid infiltration increased by 3.8-fold in the red region of the GA of mice with myosteatosis (P < 0.001). RORα was expressed around MyHC2a fibres, and its level increased by 2.7-fold after HFD feeding (P < 0.01). Second, treatment of RORα ligands in C2C12 myoblasts, such as cholesterol sulfate and JC1-40, enhanced the number of oxidative fibres stained for MyHC1 and MyHC2a by two-fold to four-fold (P < 0.01), while it reduced the lipid levels in MyHC2a fibres by 20-50% (P < 0.001) in the presence of palmitic acids. Third, mitochondrial membrane potential (P < 0.01) and total area of mitochondria (P < 0.01) were enhanced by treatment of these ligands. Chromatin immunoprecipitation analysis showed that RORα bound the promoter of GA-binding protein α subunit gene that led to activation of mitochondrial transcription factor A (TFAM) in C2C12 myoblasts (P < 0.05). Finally, intramuscular transduction of AAV-RORα alleviated the HFD-induced myosteatosis with fatty atrophy; lipid contents in MyHC2a fibres decreased by 48% (P < 0.001), whereas the number of MyHC2b fibre increased by 22% (P < 0.001). Also, administration of JC1-40 improved the signs of myosteatosis in that it decreased the level of adipose differentiation-related protein (P < 0.01) but increased mitochondrial proteins such as cytochrome c oxidase 4 and TFAM in GA muscle (P < 0.01)., Conclusions: RORα plays a versatile role in regulating the quantity of mitochondria and the oxidative capacity, ultimately leading to an improvement in myosteatosis symptoms., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

The thymus is an energy-consuming organ, and its metabolism changes with atrophy. Testosterone regulates thymus remodeling (atrophy and regeneration). However, the characteristics of the energy metabolism during testosterone-mediated thymic atrophy and regeneration remain unclear. In this study, we demonstrated that testosterone ablation (implemented by immunocastration and surgical castration) induced global metabolic changes in the thymus. Kyoto Encyclopedia of Genes and Genomes pathway enrichment for differential metabolites and metabolite set enrichment analysis for total metabolites revealed that testosterone ablation affected thymic glycolysis, glutamate metabolism, and fatty acid β-oxidation. Testosterone ablation-induced thymic regeneration was accompanied by attenuated glycolysis and glutamate metabolism and changed fatty acid composition and content. Testosterone supplementation in immunocastrated and surgically castrated rats enhanced glutaminolysis, reduced the level of unsaturated fatty acids, enhanced the β-oxidation of unsaturated fatty acids in the mitochondria, boosted the tricarboxylic acid (TCA) cycle, and accelerated thymic atrophy. Overall, these results imply that metabolic reprogramming is directly related to thymic remodeling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Corticobasal syndrome (CBS) is associated with diverse underlying pathologies, including the four-repeat (4R)-tauopathies. The Movement Disorders Society (MDS) criteria for progressive supranuclear palsy (PSP) proposed the novel category "probable 4R-tauopathy" to address the phenotypic overlap between PSP and corticobasal degeneration (CBD)., Objectives: To investigate the clinical ability of the MDS-PSP criteria for probable 4R-tauopathy in predicting a negative amyloid-PET in CBS. Additionally, this study aims to explore CBS patients classified as 4R-tauopathy concerning their clinical features and neuroimaging degeneration patterns., Methods: Thirty-two patients with probable CBS were prospectively evaluated and split into those who fulfilled or did not fulfill the 4R-tauopathy criteria (CBS-4RT+ vs. CBS-4RT-). All patients underwent positron emission tomographies (PET) with [ 18 F]fluorodeoxyglucose and [ 11 C]Pittsburgh Compound-B (PIB) on a hybrid PET-MRI scanner to perform multimodal quantitative comparisons with a control group., Results: Eleven patients were clinically classified as CBS-4RT+, and only one had a positive PIB-PET. The CBS-4RT+ classification had 92% specificity, 52% sensitivity, and 69% accuracy in predicting a negative PIB-PET. The CBS-4RT+ group presented with dysarthria and perseveration more often than the CBS-4RT- group. Moreover, the CBS-4RT+ group showed a prominent frontal hypometabolism extending to the supplementary motor area and striatum, and brain atrophy at the anterior cingulate and bilateral striata., Conclusions: The 4R-tauopathy criteria were highly specific in predicting a negative amyloid-PET in CBS. Patients classified as 4R-tauopathy presented distinct clinical aspects, as well as brain metabolism and atrophy patterns previously associated with tauopathies., (© 2023 International Parkinson and Movement Disorder Society.)

Background: Aminoacylase-1 deficiency (ACY1D) is an autosomal recessive rare inborn error of metabolism, which is caused by disease-causing variants in the ACY1. This disorder is characterized by increased urinary excretion of specific N-acetyl amino acids. Affected individuals demonstrate heterogeneous clinical manifestations which are primarily neurologic problems. In neuroimaging, corpus callosum hypoplasia, cerebellar vermis atrophy, and delayed myelination of cerebral white matter have been reported., Aims: Finding disease-causing variant and expanding imaging findings in a patient with persistent basal ganglia involvement., Methods: Whole-exome sequencing was performed in order to identify disease-causing variants in an affected 5-year-old male patient who presented with neurologic regression superimposed on neurodevelopmental delay following a febrile illness. He had inability to walk, cognitive impairment, speech delay, febrile-induced seizures, truncal hypotonia, moderate to severe generalized dystonia, and recurrent metabolic decompensation., Results: All metabolic tests were normal except for a moderate metabolic acidosis following febrile illnesses. The results of serial brain magnetic resonance imaging (MRI) at ages 1 and 4.5 years revealed persistent bilateral and symmetric abnormal signals in basal ganglia mainly caudate and globus pallidus nuclei with progression over time in addition to a mild supratentorial atrophy. A homozygous missense variant [NM&#95;000666.3: c.1057C>T; p.(Arg353Cys)] was identified in the ACY1, consistent with aminoacylase-1 deficiency. Variant confirmation in patient and segregation analysis in his family were performed using Sanger sequencing., Conclusions: Our findings expanded the phenotype spectrum of ACY1-related neurodegeneration by demonstrating persistent basal ganglia involvement and moderate to severe generalized dystonia., (© 2023. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Tau is a microtubule-associated protein that is enriched in the axonal process of neurons. Post-translational modifications of tau have been implicated in the development of tauopathies characterized by defects in axonal transport, neuronal atrophy, and microtubule disassembly. Although tau is almost quantitatively bound to microtubules under physiological conditions, it does not significantly affect axonal transport. Furthermore, acute or chronic tau deficiency does not result in significant destabilization of neuronal microtubules, challenging the classical view that disease-related tau modifications directly cause axonal microtubule collapse. Here, we discuss how the rapid interaction kinetics of the tau-microtubule interaction, which we previously termed the kiss-and-hop interaction, explains why tau does not affect microtubule-dependent axonal transport but still allows tau to modulate microtubule polymerization. In contrast, tau modifications that slow down the kinetics of the tau-microtubule interaction and increase the residence time of tau at a microtubule interaction site can disrupt axonal transport and cause dendritic atrophy. We discuss the consequences of such a gain-of-toxicity mechanism in terms of the development of disease-modulating drugs that target the tau protein., (© 2023 The Authors. Cytoskeleton published by Wiley Periodicals LLC.)

Aim: Doxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms., Methods and Results: Mice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC. HSP47 expression was significantly upregulated in serum and in heart tissue in DOX-treated mice and in isolated cardiomyocytes. Mice with cardiac-specific HSP47 overexpression and knockdown were generated using recombinant adeno-associated virus (rAVV9) injection. Importantly, cardiac-specific HSP47 overexpression exacerbated cardiac dysfunction in DIC, while HSP47 knockdown prevented DOX-induced cardiac dysfunction, cardiac atrophy and fibrosis in vivo and in vitro. Mechanistically, we identified that HSP47 directly interacted with IRE1α in cardiomyocytes. Furthermore, we provided powerful evidence that HSP47-IRE1α complex promoted TXNIP/NLRP3 inflammasome and reinforced USP1-mediated NLRP3 ubiquitination. Moreover, NLRP3 deficiency in vivo conspicuously abolished HSP47-mediated cardiac atrophy and fibrogenesis under DOX condition., Conclusion: HSP47 was highly expressed in serum and cardiac tissue after doxorubicin administration. HSP47 contributed to long-term anthracycline chemotherapy-associated cardiac dysfunction in an NLRP3-dependent manner. HSP47 therefore represents a plausible target for future therapy of doxorubicin-induced HF., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown., Methods: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI., Results: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI., Discussion: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

How aging affects cells of the human brain active milieu remains largely unknown. Here, we analyze astrocytes and neurons in the neocortical tissue of younger (22-50 years) and older (51-72 years) adults. Aging decreases the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The protein-to-lipid ratio decreases in astrocytes and increases in neurons. Aged astrocytes show morphological atrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Atrophy correlates with the loss of gap junction coupling between astrocytes and increased input resistance. Aging is accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling is observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of cortical astrocytes, but not neurons., (© 2023. The Author(s).)

Muscle mass is balanced between hypertrophy and atrophy by cellular processes, including activation of the protein kinase B-mechanistic target of rapamycin (Akt-mTOR) signaling cascade. Stressors apart from exercise and nutrition, such as heat stress, can stimulate the heat shock protein A (HSPA) and C (HSPC) families alongside hypertrophic signaling factors and muscle growth. The effects of heat stress on HSP expression and Akt-mTOR activation in human skeletal muscle and their magnitude of activation compared with known hypertrophic stimuli are unclear. Here, we show a single session of whole body heat stress following resistance exercise increases the expression of HSPA and activation of the Akt-mTOR cascade in skeletal muscle compared with resistance exercise in a healthy, resistance-trained population. Heat stress alone may also exert similar effects, though the responses are notably variable and require further investigation. In addition, acute heat stress in C2C12 muscle cells enhanced myotube growth and myogenic fusion, albeit to a lesser degree than growth factor-mediated hypertrophy. Though the mechanisms by which heat stress stimulates hypertrophy-related signaling and the potential mechanistic role of HSPs remain unclear, these findings provide additional evidence implicating heat stress as a novel growth stimulus when combined with resistance exercise in human skeletal muscle and alone in isolated murine muscle cells. We believe these findings will help drive further applied and mechanistic investigation into how heat stress influences muscular hypertrophy and atrophy. NEW & NOTEWORTHY We show that acute resistance exercise followed by whole body heat stress increases the expression of HSPA and increases activation of the Akt-mTOR cascade in a physically active and resistance-trained population.

Thymus is necessary for lifelong immunological tolerance and immunity. It displays a distinctive epithelial complexity and undergoes age-dependent atrophy. Nonetheless, it also retains regenerative capacity, which, if harnessed appropriately, might permit rejuvenation of adaptive immunity. By characterizing cortical and medullary compartments in the human thymus at single-cell resolution, in this study we have defined specific epithelial populations, including those that share properties with bona fide stem cells (SCs) of lifelong regenerating epidermis. Thymic epithelial SCs display a distinctive transcriptional profile and phenotypic traits, including pleiotropic multilineage potency, to give rise to several cell types that were not previously considered to have shared origin. Using here identified SC markers, we have defined their cortical and medullary niches and shown that, in vitro, the cells display long-term clonal expansion and self-organizing capacity. These data substantively broaden our knowledge of SC biology and set a stage for tackling thymic atrophy and related disorders., Competing Interests: Declaration of interests P.B. and R.R. are named inventors of patent application no. P206246GB. P.B. is named inventor of patent application P124596GB. P.B. and A.G. are named inventors of patent application no. PCT/GB2019/051310., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: Purpose: Intensive care unit-acquired weakness (ICUAW) is a severe neuromuscular complication that frequently occurs in patients with sepsis. The precise molecular pathophysiology of mitochondrial calcium uptake 1 (MICU1) and mitochondrial calcium uniporter (MCU) in ICUAW has not been fully elucidated. Here, we speculate that ICUAW is associated with MICU1:MCU protein ratio-mediated mitochondrial calcium ([Ca 2+ ] m ) uptake dysfunction. Methods: Cecal ligation and perforation (CLP) was performed on C57BL/6J mice to induce sepsis. Sham-operated animals were used as controls. Lipopolysaccharide (LPS) (5 μg/mL) was used to induce inflammation in differentiated C2C12 myoblasts. Compound muscle action potential (CMAP) was detected using a biological signal acquisition system. Grip strength was measured using a grip-strength meter. Skeletal muscle inflammatory factors were detected using ELISA kits. The cross-sectional area (CSA) of the tibialis anterior (TA) muscle was detected by hematoxylin and eosin staining. Cytosolic calcium ([Ca 2+ ] c ) levels were measured using Fluo-4 AM. Adeno-associated virus (AAV) was injected into TA muscles for 4 weeks to overexpress MICU1 prophylactically. A lentivirus was used to infect C2C12 cells to increase MICU1 expression prophylactically. Findings: The results suggest that sepsis induces [Ca 2+ ] m uptake disorder by reducing the MICU1:MCU protein ratio, resulting in skeletal muscle weakness and muscle fiber atrophy. However, MICU1 prophylactic overexpression reversed these effects by increasing the MICU1:MCU protein ratio. Conclusions: ICUAW is associated with impaired [Ca 2+ ] m uptake caused by a decreased MICU1:MCU protein ratio. MICU1 overexpression improves sepsis-induced skeletal muscle weakness and atrophy by ameliorating the [Ca 2+ ] m uptake disorder., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Objectives: Local injection of glucocorticoids (GCs) into the vocal folds has been used for treating the vocal fold lesions. While the positive effects on vocal fold nodules, polyps, or scarring have been clinically reported, some concern remains around the potential adverse effects such as vocal fold atrophy, and the mechanisms remain unclear. The present study examined the histology and gene expression of locally injected GC into the vocal folds in rats., Methods: Thirteen-week-old male Sprague-Dawley rats were used in the experiments. Triamcinolone acetonide (TAA) or saline were administered repeatedly to the right vocal folds at a weekly interval, and rats were euthanized one week after the last administration for histological examination. Genetic examination was assessed hyaluronic acid (HA) metabolism at 1 or 3 days after a single TAA injection by quantitative real-time polymerase chain reaction (qRT-PCR)., Results: The group which underwent four TAA injections showed a significant decrease in HA in the lamina propria (LP), thickness of the LP and total cell numbers of the LP compared with the saline group. In contrast, there was no significant difference in the area of collagen accumulation and the thyroarytenoid muscle, although there was a tendency of atrophy of the muscle. After single injection of TAA, qRT-PCR showed a significant decrease in the expression of HA synthases, Has2 and Has3., Conclusions: The current animal study first demonstrates that repeated intracordal injection of GCs may lead to atrophy of vocal folds caused by decrease of deposition of HA in the LP and decrease of gene expression of Has., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Hypoxia inducible factor-1α (HIF-1α), as a hypoxia inducible factor, affects women's reproductive function by regulating the development and excretion of follicles. HIF-1α induces glycolysis and autophagy in the granule cells by promoting oocyte development, regulating the secretion of related angiogenic factors, and improving follicle maturity. In addition, HIF-1α promotes the process of luteinization of follicular vesicles, maintains luteal function, and finally completes physiological luteal atrophy through cumulative oxidative stress. Dysfunction of HIF-1α will cause a series of pathological consequences, such as angiogenesis defect, energy metabolism abnormality, excessive oxidative stress and dysregulated autophagy and apoptosis, resulting in ovulation problem and infertility. This article summarizes the previous studies on the regulation of follicle development and excretion and maintenance of luteal function and structural atrophy by HIF-1α. We also describe the effective intervention mechanism of related drugs or bioactive ingredients on follicular dysplasia and ovulation disorders through HIF-1α, in order to provide a systematic and in-depth insights for solving ovulation disorder infertility.

Stargardt maculopathy, caused predominantly by mutations in the ABCA4 gene, is characterized by an accumulation of non-degradable visual pigment derivative, lipofuscin, in the retinal pigment epithelium (RPE) - resulting in RPE atrophy. RPE is a monolayer tissue located adjacent to retinal photoreceptors and regulates their health and functioning; RPE atrophy triggers photoreceptor cell death and vision loss in Stargardt patients. Previously, ABCA4 mutations in photoreceptors were thought to be the major contributor to lipid homeostasis defects in the eye. Recently, we demonstrated that ABCA4 loss of function in the RPE leads to cell-autonomous lipid homeostasis defects. Our work underscores that an incomplete understanding of lipid metabolism and lipid-mediated signaling in the retina and RPE are potential causes for lacking treatments for this disease. Here we report altered lipidomic in mouse and human Stargardt models. This work provides the basis for therapeutics that aim to restore lipid homeostasis in the retina and the RPE., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Published by Elsevier Inc.)

Sodium iodate (NaIO3) induces retinal pigment epithelium (RPE) dysfunction, which leads to photoreceptor degeneration. Previously, we used electron microscopy to show that the administration of NaIO3 resulted in the accumulation of cell debris in the subretinal space, which was thought to be caused by failed phagocytosis in the outer segment of the photoreceptor due to RPE dysfunction. We further analyzed the pathological changes in the retina and choroid of NaIO3-injected mice, and found that the expression of OTX2, an RPE marker, disappeared from central part of the RPE 1 day after NaIO3 administration. Furthermore, fenestrated capillaries (choriocapillaris, CC) adjacent to the RPE could not be identified only 2 days after NaIO3 administration. An examination of the expression of the CC-specific protein plasmalemma vesicle-associated protein (PLVAP), in sections and flat-mount retina/choroid specimens showed destruction of the CC, and complete disappearance of the PLVAP signal 7 days after NaIO3 administration. In contrast, CD31 flat-mount immunohistochemistry of the retina indicated no difference in retinal vessels between NaIO3-treated mice and controls. Electron microscopy showed that the fenestrated capillaries in the kidney and duodenum were morphologically indistinguishable between control and NaIO3-treated mice. We examined cytokine production in the retina and RPE, and found that the Vegfa transcript level in the RPE decreased starting 1 day after NaIO3 administration. Taken together, these observations show that NaIO3 reduces the CC in the early stages of the pathology, which is accompanied by a rapid decrease in Vegfa expression in the RPE., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This work aimed to investigate potential pathways linking age and imaging measures to early age- and pathology-related changes in cognition. We used [18F]-Flutemetamol (amyloid) and [18F]-Flortaucipir (tau) positron emission tomography (PET), structural MRI, and neuropsychological assessment from 232 elderly individuals aged 50-89 years (46.1% women, 23% APOE-ε4 carrier, 23.3% MCI). Tau-PET was available for a subsample of 93 individuals. Structural equation models were used to evaluate cross-sectional pathways between age, amyloid and tau burden, grey matter thickness and volumes, white matter hyperintensity volume, lateral ventricle volume, and cognition. Our results show that age is associated with worse outcomes in most of the measures examined and had similar negative effects on episodic memory and executive functions. While increased lateral ventricle volume was consistently associated with executive function dysfunction, participants with mild cognitive impairment drove associations between structural measures and episodic memory. Both age and amyloid-PET could be associated with medial temporal lobe tau, depending on whether we used a continuous or a dichotomous amyloid variable. Tau burden in entorhinal cortex was related to worse episodic memory in individuals with increased amyloid burden (Centiloid >12) independently of medial temporal lobe atrophy. Testing models for sex differences revealed that amyloid burden was more strongly associated with regional atrophy in women compared with men. These associations were likely mediated by higher tau burden in women. These results indicate that influences of pathological pathways on cognition and sex-specific vulnerabilities are dissociable already in early stages of neuropathology and cognitive impairment., (© 2023. Springer Nature Limited.)

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 α 1 -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 α 1 -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.

Background: Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX., Methods: We used global PDE10A knockout (KO) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies., Results: We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA (protein kinase A)- and cGMP/PKG-dependent signaling., Conclusions: Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth., Competing Interests: Disclosures None.

Cisplatin, a platinum-based anticancer drug used frequently in cancer treatment, causes skeletal muscle atrophy. It was predicted that the proteolytic pathway is enhanced as the mechanism of this atrophy. Therefore, we investigated whether a platinum-based anticancer drug affects the expression of the major proteins of skeletal muscle, myosin heavy chain (MyHC). Mice were injected with cisplatin or oxaliplatin for four consecutive days. C2C12 myotubes were treated using cisplatin and oxaliplatin. Administration of platinum-based anticancer drug reduced quadriceps mass and muscle strength compared to the control group. Protein levels of all MyHC isoforms were reduced in the platinum-based anticancer drug groups. However, only Myh2 (MyHC-IIa) gene expression in skeletal muscle of mice treated with platinum-based anticancer drugs was found to be reduced. Treatment of C2C12 myotubes with platinum-based anticancer drugs reduced the protein levels of all MyHCs, and treatment with the proteasome inhibitor MG-132 restored this reduction. The expression of Mef2c, which was predicted to act upstream of Myh2, was reduced in the skeletal muscle of mice treated systemically with platinum-based anticancer drug. Degradation of skeletal muscle MyHCs by proteasomes may be a factor that plays an important role in muscle mass loss in platinum-based anticancer drug-induced muscle atrophy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Duchenne muscular dystrophy (DMD) is an X-linked lethal genetic disorder for which there is no effective treatment. Previous studies have shown that stem cell transplantation into mdx mice can promote muscle regeneration and improve muscle function, however, the specific molecular mechanisms remain unclear. DMD suffers varying degrees of hypoxic damage during disease progression. This study aimed to investigate whether induced pluripotent stem cells (iPSCs) have protective effects against hypoxia-induced skeletal muscle injury., Results: In this study, we co-cultured iPSCs with C2C12 myoblasts using a Transwell nested system and placed them in a DG250 anaerobic workstation for oxygen deprivation for 24 h. We found that iPSCs reduced the levels of lactate dehydrogenase and reactive oxygen species and downregulated the mRNA and protein levels of BAX/BCL2 and LC3II/LC3I in hypoxia-induced C2C12 myoblasts. Meanwhile, iPSCs decreased the mRNA and protein levels of atrogin-1 and MuRF-1 and increased myotube width. Furthermore, iPSCs downregulated the phosphorylation of AMPKα and ULK1 in C2C12 myotubes exposed to hypoxic damage., Conclusions: Our study showed that iPSCs enhanced the resistance of C2C12 myoblasts to hypoxia and inhibited apoptosis and autophagy in the presence of oxidative stress. Further, iPSCs improved hypoxia-induced autophagy and atrophy of C2C12 myotubes through the AMPK/ULK1 pathway. This study may provide a new theoretical basis for the treatment of muscular dystrophy in stem cells., (© 2023. The Author(s).)

Emerging evidence indicates that vascular stress is an important contributor to the pathophysiology of Alzheimer's disease and related dementias (ADRD). Hydrogen sulfide (H 2 S) and its metabolites (acid-labile (e.g., iron-sulfur clusters) and bound (e.g., per-, poly-) sulfides) have been shown to modulate both vascular and neuronal homeostasis. We recently reported that elevated plasma sulfides were associated with cognitive dysfunction and measures of microvascular disease in ADRD. Here we extend our previous work to show associations between elevated sulfides and magnetic resonance-based metrics of brain atrophy and white matter integrity. Elevated bound sulfides were associated with decreased grey matter volume, while increased acid labile sulfides were associated with decreased white matter integrity and greater ventricular volume. These findings are consistent with alterations in sulfide metabolism in ADRD which may represent maladaptive responses to oxidative stress., Competing Interests: Declaration of competing interest The authors have no conflicts to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To explore the effects and mechanism of millimeter-wave treatment on the development of joint stiffness in the immobilized knee rat model., Methods: Twenty-four Sprague-Dawley (SD) rats were randomly divided into the control group (O, n = 8), the surgical control group (OC, n = 8), and the millimeter-wave treatment group (MO, n = 8). After immobilized knee modeling, the knee mobility and quadriceps diameter was measured at the 6th week. Hematoxylin and eosin and Masson staining were performed to detect the pathology and fibrous lesions of the knee joint. Furthermore, the expression of TGF-β1 and Collagen I was quantified by immunohistochemical assay in the knee capsule, and Western blotting was performed to quantify the protein expression of NF-κB and MuRF1 in skeletal muscle., Results: Compared with the O group, knee mobility, and quadriceps diameter was decreased (P < 0.01), and articular capsule fibrosis and quadriceps atrophy occurred in all rats with fixed knee joints. Compared with the OC group, millimeter-wave treatment significantly increased articular mobility and the quadriceps diameter; and improved the fibrotic lesions of the joint capsule and quadriceps atrophy. Moreover, levels of TGF-β1, Collagen I, and MuRF1 were upregulated (P < 0.01) by knee immobilization, and collagen fiber content in the articular capsule was also increased (P < 0.01). However, millimeter-wave treatment reversed it. The most noteworthy result was that NF-κB expression was not significantly different in all groups., Conclusion: Millimeter-wave treatment reversed joint contracture and quadriceps atrophy caused by joint fixation, inhibited TGF-β1 and Collagen I protein expression of the joint capsule and reduced MuRF1 expression of the quadriceps muscle, thereby inhibiting the development of joint stiffness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Astrocyte atrophy is the main histopathological hallmark of major depressive disorder (MDD) in humans and in animal models of depression. Here we show that electroacupuncture prevents astrocyte atrophy in the prefrontal cortex and alleviates depressive-like behaviour in mice subjected to chronic unpredictable mild stress (CUMS). Treatment of mice with CUMS induced depressive-like phenotypes as confirmed by sucrose preference test, tail suspension test, and forced swimming test. These behavioural changes were paralleled with morphological atrophy of astrocytes in the prefrontal cortex, revealed by analysis of 3D reconstructions of confocal Z-stack images of mCherry expressing astrocytes. This morphological atrophy was accompanied by a decrease in the expression of cytoskeletal linker Ezrin, associated with formation of astrocytic leaflets, which form astroglial synaptic cradle. Electroacupuncture at the acupoint ST36, as well as treatment with anti-depressant fluoxetine, prevented depressive-like behaviours, astrocytic atrophy, and down-regulation of astrocytic ezrin. In conclusion, our data further strengthen the notion of a primary role of astrocytic atrophy in depression and reveal astrocytes as cellular target for electroacupuncture in treatment of depressive disorders., (© 2023. The Author(s).)

Aging is associated with muscle atrophy, and erosion and destruction of neuronal pathways in the spinal cord. The study aim was to assess the effect of swimming training (Sw) and L-arginine loaded chitosan nanoparticles (LA-CNPs) on the sensory and motor neuron population, autophagy marker LC3, total oxidant status/total antioxidant capacity, behavioural test, GABA and BDNF-TrkB pathway in the spinal cord of aging rats. The rats were randomized to five groups: young (8-weeks) control (n = 7), old control (n = 7), old Sw (n = 7), old LA-CNPs (n = 7) and old Sw + LA-CNPs (n = 7). Groups under LA-CNPs supplementation received 500 mg/kg/day. Sw groups performed a swimming exercise programme 5 days per week for 6 weeks. Upon the completion of the interventions the rats were euthanized and the spinal cord was fixed and frozen for histological assessment, IHC, and gene expression analysis. The old group had more atrophy in the spinal cord with higher changes in LC3 as an indicator of autophagy in the spinal cord compared to the young group (p < 0.0001). The old Sw + LA-CNPs group increased (improved) spinal cord GABA (p = 0.0187), BDNF (p = 0.0003), TrkB (p < 0.0001) gene expression, decreased autophagy marker LC3 protein (p < 0.0001), nerve atrophy and jumping/licking latency (p < 0.0001), improved sciatic functional index score and total oxidant status/total antioxidant capacity compared to the old group (p < 0.0001). In conclusion, swimming and LA-CNPs seems to ameliorate aging-induced neuron atrophy, autophagy marker LC3, oxidant-antioxidant status, functional restoration, GABA and BDNF-TrkB pathway in the spinal cord of aging rats. Our study provides experimental evidence for a possible positive role of swimming and L-arginine loaded chitosan nanoparticles to decrease complications of aging., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Skeletal muscle dysfunction in chronic obstructive pulmonary disease (COPD) is characterized by a significant reduction in muscle strength and endurance. Preclinical studies show that stimulation of the soluble guanylate cyclase (sGC)-cGMP pathway attenuates muscle mass loss and prevents cigarette smoke-induced oxidative stress, indicating that pharmacological activation of the guanylyl cyclase pathway in COPD may provide a beneficial therapeutic strategy that reaches beyond the lung. In this study, conducted in an animal model of COPD, we first set out to assess the effect of cigarette smoke (CS) on biomarkers of muscle fatigue, such as protein degradation and its transcriptional regulation, in two types of muscles with different energy demands, i.e., the diaphragm and the gastrocnemius muscle of the limbs. Second, we evaluated the administration of an sGC stimulator on these markers to study the potential efficacy of such treatment in the recovery of skeletal muscle function. Exposure to CS led to weight loss, which was associated in the gastrocnemius with increased levels of proteolytic markers of muscle atrophy (MURF-1, Atrogin-1, proteasome C8 subunit 20 s, and total protein ubiquitination), whereas the size of fast-twitch muscle fibers decreased significantly. Long-term treatment with the sGC stimulator BAY 41-2272 resulted in a significant reduction in gastrocnemius levels of the aforementioned proteolytic markers, concomitant with a weight recovery and increased cGMP levels. Remarkably, levels of some of the analyzed biomarkers differed between respiratory and limb muscles. In conclusion, targeting sGC might exert beneficial effects on muscle alterations in patients with COPD.

Pregnancy causes abrupt thymic atrophy. This atrophy is characterized by a severe decrease in the number of all thymocyte subsets and qualitative (but not quantitative) changes in thymic epithelial cells (TECs). Pregnancy-related thymic involution is triggered by progesterone-induced functional changes affecting mainly cortical TECs (cTECs). Remarkably, this severe involution is rapidly corrected following parturition. We postulated that understanding the mechanisms of pregnancy-related thymic changes could provide novel insights into signaling pathways regulating TEC function. When we analyzed genes whose expression in TECs was modified during late pregnancy, we found a strong enrichment in genes bearing KLF4 transcription factor binding motifs. We, therefore, engineered a Psmb11-iCre : Klf4 lox/lox mouse model to study the impact of TEC-specific Klf4 deletion in steady-state conditions and during late pregnancy. Under steady-state conditions, Klf4 deletion had a minimal effect on TEC subsets and did not affect thymic architecture. However, pregnancy-induced thymic involution was much more pronounced in pregnant females lacking Klf4 expression in TECs. These mice displayed a substantial ablation of TECs with a more pronounced loss of thymocytes. Transcriptomic and phenotypic analyses of Klf4 -/- TECs revealed that Klf4 maintains cTEC numbers by supporting cell survival and preventing epithelial-to-mesenchymal plasticity during late pregnancy. We conclude that Klf4 is essential for preserving TEC's integrity and mitigating thymic involution during late pregnancy., Competing Interests: Author MD-L was employed by the companies ExCell Thera, Inc. and Piercing Star Technologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Depoërs, Dumont-Lagacé, Trinh, Houques, Côté, Larouche, Brochu and Perreault.)

Environmental enteric dysfunction (EED) is characterized by malabsorption and diarrhea that result in irreversible deficits in physical and intellectual growth. We sought to define the expression of transport and tight junction proteins by quantitative analysis of duodenal biopsies from patients with EED. Biopsies from Pakistani children with confirmed EED diagnoses were compared to those from age-matched North American healthy controls, patients with celiac disease, and patients with nonceliac disease with villous atrophy or intraepithelial lymphocytosis. Expression of brush border digestive and transport proteins and paracellular (tight junction) proteins was assessed by quantitative multiplex immunofluorescence microscopy. EED was characterized by partial villous atrophy and marked intraepithelial lymphocytosis. Epithelial proliferation and enteroendocrine, tuft, and Paneth cell numbers were unchanged, but there was significant goblet cell expansion in EED biopsies. Expression of proteins involved in nutrient and water absorption and that of the basolateral Cl - transport protein NKCC1 were also increased in EED. Finally, the barrier-forming tight junction protein claudin-4 (CLDN4) was significantly upregulated in EED, particularly within villous enterocytes. In contrast, expression of CFTR, CLDN2, CLDN15, JAM-A, occludin, ZO-1, and E-cadherin was unchanged. Upregulation of a barrier-forming tight junction protein and brush border and basolateral membrane proteins that support nutrient and water transport in EED is paradoxical, as their increased expression would be expected to be correlated with increased intestinal barrier function and enhanced absorption, respectively. These data suggest that EED activates adaptive intestinal epithelial responses to enhance nutrient absorption but that these changes are insufficient to restore health., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Most cells in the body are mononuclear whereas skeletal muscle fibres are uniquely multinuclear. The nuclei of muscle fibres (myonuclei) are usually situated peripherally which complicates the equitable distribution of gene products. Myonuclear abundance can also change under conditions such as hypertrophy and atrophy. Specialised zones in muscle fibres have different functions and thus distinct synthetic demands from myonuclei. The complex structure and regulatory requirements of multinuclear muscle cells understandably led to the hypothesis that myonuclei govern defined 'domains' to maintain homeostasis and facilitate adaptation. The purpose of this review is to provide historical context for the myonuclear domain and evaluate its veracity with respect to mRNA and protein distribution resulting from myonuclear transcription. We synthesise insights from past and current in vitro and in vivo genetically modified models for studying the myonuclear domain under dynamic conditions. We also cover the most contemporary knowledge on mRNA and protein transport in muscle cells. Insights from emerging technologies such as single myonuclear RNA-sequencing further inform our discussion of the myonuclear domain. We broadly conclude: (1) the myonuclear domain can be flexible during muscle fibre growth and atrophy, (2) the mechanisms and role of myonuclear loss and motility deserve further consideration, (3) mRNA in muscle is actively transported via microtubules and locally restricted, but proteins may travel far from a myonucleus of origin and (4) myonuclear transcriptional specialisation extends beyond the classic neuromuscular and myotendinous populations. A deeper understanding of the myonuclear domain in muscle may promote effective therapies for ageing and disease., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

In vitro models provide an important platform for the investigation of cellular growth and atrophy to inform, or extend mechanistic insights from, logistically challenging in vivo trials. Although these models allow for the identification of candidate mechanistic pathways, many models involve supraphysiological dosages, nonphysiological conditions, or experimental changes relating to individual proteins or receptors, all of which limit translation to human trials. To overcome these drawbacks, the use of ex vivo human plasma and serum has been used in cellular models to investigate changes in myotube hypertrophy, cellular protein synthesis, anabolic and catabolic markers in response to differing age, disease states, and nutrient status. However, there are currently no concurrent guidelines outlining the optimal methodology for this model. This review discusses the key methodological considerations surrounding the use of ex vivo plasma and serum with a focus in application to skeletal muscle cell lines (i.e., C2C12, L6, and LHCN-M2) and human primary skeletal muscle cells (HSMCs) as a means to investigate molecular signaling in models of atrophy and hypertrophy, alongside future directions.

Upwelling oceanographic phenomenon is associated with increased food availability, low seawater temperature and pH. These conditions could significantly affect food quality and, in consequence, the growth of marine species. One of the most important organismal traits is somatic growth, which is highly related to skeletal muscle. In fish, skeletal muscle growth is highly influenced by environmental factors (i.e. temperature and nutrient availability) that showed differences between upwelling and downwelling zones. Nevertheless, there are no available field studies regarding the impact of those conditions on fish muscle physiology. This work aimed to evaluate the muscle fibers size, protein content, gene expression of growth and atrophy-related genes in fish sampled from upwelling and downwelling zones. Seawater and fish food items (seaweeds) samples were collected from upwelling and downwelling zones to determine the habitat's physical-chemical variations and the abundance of biomolecules in seaweed tissue. In addition, white skeletal muscle samples were collected from an intertidal fish to analyze muscular histology, the growth pathways of protein kinase B and the extracellular signal-regulated kinase; and the gene expression of growth- (insulin-like growth factor 1 and myosin heavy-chain) and atrophy-related genes (F-box only protein 32 and muscle RING-finger protein-1). Upwelling zones revealed higher nutrients in seawater and higher protein content in seaweed than samples from downwelling zones. Moreover, fish from upwelling zones presented a greater size of muscle fibers and protein content compared to downwelling fish, associated with lower protein ubiquitination and gene expression of F-box only protein 32. Our data indicate an attenuated use of proteins as energy source in upwelling conditions favoring protein synthesis and muscle growth. This report shed lights of how oceanographic conditions may modulate food quality and fish muscle physiology in an integrated way, with high implications for marine conservation and sustainable fisheries management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background and Goals: There are currently no standard treatments for chronic atrophic gastritis and traditional Chinese medicine may be effective. This study aims to investigate the efficacy and safety of Weierkang pills in treating chronic atrophic gastritis., Materials and Methods: There were 108 patients in our study. They were randomly assigned to 2 groups. In group A, patients received Weierkang pills and patients in group B received folic acid combined with teprenone. Symptoms, endoscopic scores, and biopsy specimens were compared at baseline and 3 months after treatment. Meanwhile, the expressions of vascular endothelial growth factor and trefoil factor 3 (TFF3) in biopsy specimens were also compared., Results: Our study showed that the total effective rates of atrophy/intestinal metaplasia in group A reached the same level as group B (51.7% vs. 40.0%, P =0.419). Weierkang significantly improved the total effective rate of atrophy/intestinal metaplasia in gastric angle compared with group B (64.7% vs. 33.3%, P =0.024). Weierkang can significantly lower the total Kyoto risk score (2.6±1.1 vs. 3.3±1.0, P =0.002) and atrophy score (1.4±0.6 vs. 1.8±0.5, P =0.001) after treatment. In addition, Weierkang improves symptoms (1.3±1.3 vs. 2.3±1.8, P =0.003) and epigastric pain (0.2±0.4 vs. 0.5±0.6, P =0.041). The expression of TFF3 in gastric mucosa decreased significantly after treatment with Weierkang ( P =0.002)., Conclusions: Weierkang can improve the endoscopic appearance and pathologic changes of chronic atrophic gastritis patients. Symptoms also improved. TFF3 may be involved the pathophysiology mechanism., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene ( SMN1 ). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.

Introduction: Studies are lacking in evaluating brain atrophy patterns in the Malaysian population. This study aimed to compare the patterns of cerebral atrophy and impaired glucose metabolism on 18 F-FDG PET/CT imaging in various stages of AD in a Klang Valley population by using voxelbased morphometry in SPM12., Materials and Methods: 18 F-FDG PET/CT images of 14 healthy control (HC) subjects (MoCA score > 26 (mean+SD~ 26.93+0.92) with no clinical evidence of cognitive deficits or neurological disease) and 16 AD patients (MoCA ≤22 (mean+SD~18.6+9.28)) were pre-processed in SPM12 while using our developed Malaysian healthy control brain template. The AD patients were assessed for disease severity using ADAS-Cog neuropsychological test. KNE96 template was used for registration-induced deformation in comparison with the ICBM templates. All deformation fields were corrected using the Malaysian healthy control template. The images were then nonlinearly modified by DARTEL to segment grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) to produce group-specific templates. Age, intracranial volume, MoCA score, and ADASCog score were used as variables in two sample t test between groups. The inference of our brain analysis was based on a corrected threshold of p<0.001 using Z-score threshold of 2.0, with a positive value above it as hypometabolic. The relationship between regional atrophy in GM and WM atrophy were analysed by comparing the means of cortical thinning between normal control and three AD stages in 15 clusters of ROI based on Z-score less than 2.0 as atrophied., Results: One-way ANOVA indicated that the means were equal for TIV, F(2,11) = 1.310, p=0.309, GMV, F(2,11) = 0.923, p=0.426, WMV, F(2,11) = 0.158, p=0.856 and CSF, F(2,11) = 1.495 p=0.266. Pearson correlations of GM, WM and CSF volume between HC and AD groups indicated the presence of brain atrophy in GM (p=-0.610, p<0.0001), WM (p=-0.178, p=0.034) and TIV (p=-0.374, p=0.042) but showed increased CSF volume (p=0.602, p<0.0001). Voxels analysis of the 18FFDG PET template revealed that GM atrophy differs significantly between healthy control and AD (p<0.0001). Zscore comparisons in the region of GM & WM were shown to distinguish AD patients from healthy controls at the prefrontal cortex and parahippocampal gyrus. The atrophy rate within each ROI is significantly different between groups (c 2 =35.9021, df=3, p<0.0001), Wilcoxon method test showed statistically significant differences were observed between Moderate vs. Mild AD (p<0.0001), Moderate AD vs. healthy control (p=0.0005), Mild AD vs. HC (p=0.0372) and Severe AD vs. Moderate AD (p<0.0001). The highest atrophy rate within each ROI between the median values ranked as follows severe AD vs. HC (p<0.0001) > mild AD vs. HC (p=0.0091) > severe AD vs. moderate AD (p=0.0143)., Conclusion: We recommend a reliable method in measuring the brain atrophy and locating the patterns of hypometabolism using a group-specific template registered to a quantitatively validated KNE96 group-specific template. The studied regions together with neuropsychological test approach is an effective method for the determination of AD severity in a Malaysian population.

Muscle weakness and wasting are defining features of cancer-induced cachexia. Mitochondrial stress occurs before atrophy in certain muscles, but the possibility of heterogeneous responses between muscles and across time remains unclear. Using mice inoculated with Colon-26 cancer, we demonstrate that specific force production was reduced in quadriceps and diaphragm at 2 weeks in the absence of atrophy. At this time, pyruvate-supported mitochondrial respiration was lower in quadriceps while mitochondrial H2O2 emission was elevated in diaphragm. By 4 weeks, atrophy occurred in both muscles, but specific force production increased to control levels in quadriceps such that reductions in absolute force were due entirely to atrophy. Specific force production remained reduced in diaphragm. Mitochondrial respiration increased and H2O2 emission was unchanged in both muscles versus control while mitochondrial creatine sensitivity was reduced in quadriceps. These findings indicate muscle weakness precedes atrophy and is linked to heterogeneous mitochondrial alterations that could involve adaptive responses to metabolic stress. Eventual muscle-specific restorations in specific force and bioenergetics highlight how the effects of cancer on one muscle do not predict the response in another muscle. Exploring heterogeneous responses of muscle to cancer may reveal new mechanisms underlying distinct sensitivities, or resistance, to cancer cachexia.

In Brief: Maternal obesity plus high-fat diet in breastfeeding induces stromal hyperplasia and diffuse acinar atrophy in the rat prostate at aging, related to dyslipidemia and testosterone reduction. The high-lipid nutritional environment from intrauterine and throughout life favors the development of prostatic intraepithelial neoplasia and aggravated degenerative alterations in the gland., Abstract: Maternal obesity and high-fat diet (HFD) affect permanently prostate histophysiology in adulthood, but the consequences during aging are unknown. Here, we evaluated the prostate alterations in middle-aged rats subjected to a high-lipid nutritional environment (HLE) in different ontogenetic periods. Wistar rats (56 weeks of age) were assigned into groups exposed to standard nutrition (C) or HLE during gestation (G), gestation and lactation (GL), from lactation onward (L), from weaning onward (W) and from gestation onward (AL). HLE in the periods after weaning consisted of HFD (20% fat), and during gestation and lactation it also included previous maternal obesity induced by the HFD. HLE increased total cholesterol and triglyceride levels in all groups and led to insulin resistance in GL and AL and obesity in L. Serum testosterone levels decreased ~67% in GL, ~146% in L and W, and ~233% in AL. Histological and stereological analysis revealed an increment of the stromal compartment and collagen fibers in the prostates of all HLE groups, as well as degenerative lesions, such as cell vacuolation and prostate concretions. HLE aggravated acinar atrophy in G, GL, and L, and in AL it reached more than 50% of the prostate area for most animals. The foci of prostatic intraepithelial neoplasia increased in AL. Tissue expression of androgen receptor did not vary among groups, except for a higher stromal expression for G and GL. Even when restricted to gestation and lactation, HLE induces diffuse acinar atrophy in the aging prostate and worsens degenerative and premalignant lesions when it continues throughout life.

Skin aging is a major risk factor for the dermal diseases, and interventions to attenuate cellular senescence are expected to reduce the risk for age-related diseases involving skin atrophy. However, blocking cell death or extending proliferation causally results in side effects and an increased cancer risk. For identification of a safer approach, we focused on PDK1 inhibition, which could revert cellular senescence and reduce senescence factors in skin in vitro, in a human skin equivalent model and in an exploratory, placebo-controlled, interventional trial. Natural phytochemical kaempferol tetrasaccharides resulted in a significant reduction in cellular senescence, and an increase in collagen fiber was observed in the skin cell and human skin equivalent. Clinical enhancement in skin appearance was noted in multiple participants, and an immunohistochemical study revealed improvement in the histological appearance of skin tissue and extracellular matrix. This change was associated with relative improvement in histological markers of senescence and clinical appearance of the aged skin and an increase in collagen fiber, an essential factor for preventing skin atrophy and consistency of the basement membrane. These results indicate that PDK1 inhibition is a potentially effective antiaging intervention, suggesting a diagnostic role and preventive actions of PDK1 in senescence-associated skin atrophy., Competing Interests: Conflict of Interest The authors have no relevant financial or nonfinancial interests to disclose., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Type 2 DM is a risk factor for dementia, including Alzheimer's disease (AD), and is associated with brain atrophy. Amyloid β protein (Aβ) deposition in the brain parenchyma is implicated in the neurodegeneration that occurs in AD. Platelets, known as abundant storage of Aβ, are recognized to play important roles in the onset and progression of AD. We recently showed that Aβ negatively regulates platelet activation induced by thrombin receptor-activating protein (TRAP) in healthy people. In the present study, we investigated the effects of Aβ on the TRAP-stimulated platelet activation in DM patients, and the relationship between the individual responsiveness to Aβ and quantitative findings of MRI, the volume of white matter hyperintensity (WMH)/intracranial volume (IC) and the volume of parenchyma (PAR)/IC. In some DM patients, Aβ reduced platelet aggregation induced by TRAP, while in others it was unchanged or rather enhanced. The TRAP-induced levels of phosphorylated-Akt and phosphorylated-HSP27, the levels of PDGF-AB and the released phosphorylated-HSP27 correlated with the degree of platelet aggregability. The individual levels of not WMH/IC but PAR/IC was correlated with those of TRAP-stimulated PDGF-AB release. Collectively, our results suggest that the reactivity of TRAP-stimulated platelet activation to Aβ differs in DM patients from healthy people. The anti-suppressive feature of platelet activation to Aβ might be protective for brain atrophy in DM patients.

Cases of neglect in dogs are among the forensic cases submitted most commonly for postmortem examination. Starvation is a form of primary protein-energy malnutrition in which the availability of food is severely restricted or absent; cachexia is a form of protein-energy malnutrition secondary to progressive metabolic derangement during chronic diseases. Despite both conditions leading to an emaciated appearance of the cadaver, discrimination between the two is crucial in forensic cases. We hypothesized that among emaciated dogs, the degree of liver atrophy in starved animals is higher than in cachectic ones, and that this can be investigated microscopically, regardless of the degree of cadaver decomposition. We studied 46 animals: 23 starved, 11 cachectic, and 12 control dogs. Portal tracts were identified by the presence of a bile duct and associated vascular structures recognizable by a thin rim of collagen still visible regardless of the degree of cadaver decomposition. The number of portal tracts per lpf (10×) was used as an indirect measure of atrophy. The number of portal tracts in starved dogs was significantly higher ( p < 0.01) compared to both cachectic and control dogs, indicating a higher degree of liver atrophy in starvation. Measuring the density of portal tracts offers a reliable additional tool for discrimination between starvation and cachexia.

Purpose: We have demonstrated that deletion of fibroblast growth factor receptor 2 gene (Fgfr2) leads to Meibomian gland (MG) atrophy in an inducible conditional knockout mouse model, referred as Fgfr2 CKO . Herein, we investigated whether MG spontaneously recovers after atrophy in this model., Methods: Two months old Fgfr2 CKO mice were injected peritoneally once or twice of doxycycline (Dox) at 80 μg/gm of body weight to induce MG atrophy of various severities via Fgfr2 deletion. Recovery of acinar and ductal tissues was monitored by meibography, lipid staining and immunofluorescence against keratin-6a in MG whole-mount. Biomarkers for acinar and ductal differentiation and proliferation were also examined by immunostaining., Results: Single Dox injection in Fgfr2 CKO mice caused severe acinar and moderate ductal atrophy. Severe ductal shortening or loss occurred after second Dox injection, presumably related to the reported slower cycling of the ductal epithelia. Spontaneous acinar regrowth after atrophy was observed over a period of 60 days in both injection regimens. However, less robust acinar recovery was associated with more disrupted ductal structures in twice injected Fgfr2 CKO mice., Conclusions: Our current findings further substantiate the role of FGFR2 in MG homeostasis, and suggest that FGFR2-signaling may provide a potential strategy for regenerating acini from age-related MG dysfunction in humans. Our data demonstrated that spontaneous MG recovery depends on the extent of ductal atrophy, suggesting that ductal epithelia may provide the progenitor cells for acinar regeneration. Nonetheless, the role of ductal tissue as the source of acinar progenitors awaits further investigation., Competing Interests: Declaration of competing interest The authors have no commercial interest in any concept or product discussed in this article., (Copyright © 2021. Published by Elsevier Inc.)

Background: Activation of sphingomyelinase (SMase) as a result of a general inflammatory response has been implicated as a mechanism underlying disease-related loss of skeletal muscle mass and function in several clinical conditions including heart failure. Here, for the first time, we characterize the effects of SMase activity on human muscle fibre contractile function and assess skeletal muscle SMase activity in heart failure patients., Methods: The effects of SMase on force production and intracellular Ca 2+ handling were investigated in single intact human muscle fibres. Additional mechanistic studies were performed in single mouse toe muscle fibres. RNA sequencing was performed in human muscle bundles exposed to SMase. Intramuscular SMase activity was measured from heart failure patients (n = 61, age 69 ± 0.8 years, NYHA III-IV, ejection fraction 25 ± 1.0%, peak VO 2 14.4 ± 0.6 mL × kg × min) and healthy age-matched control subjects (n = 10, age 71 ± 2.2 years, ejection fraction 60 ± 1.2%, peak VO 2 25.8 ± 1.1 mL × kg × min). SMase activity was related to circulatory factors known to be associated with progression and disease severity in heart failure., Results: Sphingomyelinase reduced muscle fibre force production (-30%, P < 0.05) by impairing sarcoplasmic reticulum (SR) Ca 2+ release (P < 0.05) and reducing myofibrillar Ca 2+ sensitivity. In human muscle bundles exposed to SMase, RNA sequencing analysis revealed 180 and 291 genes as up-regulated and down-regulated, respectively, at a FDR of 1%. Gene-set enrichment analysis identified 'proteasome degradation' as an up-regulated pathway (average fold-change 1.1, P = 0.008), while the pathway 'cytoplasmic ribosomal proteins' (average fold-change 0.8, P < 0.0001) and factors involving proliferation of muscle cells (average fold-change 0.8, P = 0.0002) where identified as down-regulated. Intramuscular SMase activity was ~20% higher (P < 0.05) in human heart failure patients than in age-matched healthy controls and was positively correlated with markers of disease severity and progression, and with several circulating inflammatory proteins, including TNF-receptor 1 and 2. In a longitudinal cohort of heart failure patients (n = 6, mean follow-up time 2.5 ± 0.2 years), SMase activity was demonstrated to increase by 30% (P < 0.05) with duration of disease., Conclusions: The present findings implicate activation of skeletal muscle SMase as a mechanism underlying human heart failure-related loss of muscle mass and function. Moreover, our findings strengthen the idea that SMase activation may underpin disease-related loss of muscle mass and function in other clinical conditions, acting as a common patophysiological mechanism for the myopathy often reported in diseases associated with a systemic inflammatory response., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Kushwaha, Asha D., and Deepika Saraswat. A nanocurcumin and pyrroloquinoline quinone formulation prevents hypobaric hypoxia-induced skeletal muscle atrophy by modulating NF-κB signaling pathway. High Alt Med Biol . 23:249-263, 2022. Background: Hypobaric hypoxia (HH)-induced deleterious skeletal muscle damage depends on exposure time and availability of oxygen at cellular level, which eventually can limit human work performance at high altitude (HA). Despite the advancements made in pharmacological (performance enhancer, antioxidants) and nonpharmacological therapeutics (acclimatization strategies), only partial success has been achieved in improving physical performance at HA. A distinctive combination of nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) has been formulated (named NCF [nanocurcumin formulation], Indian patent No. 302877) in our laboratory, and has proven very promising in improving cardiomyocyte adaptation to chronic HH. We hypothesized that NCF might improve skeletal muscle adaptation and could be a performance enhancer at HA. Material and Methods: Adult Sprague-Dawley rats (220 ± 10 g) were divided into five groups ( n  = 6/group): normoxia vehicle control, hypoxia vehicle control, hypoxia NCF, hypoxia NC, and hypoxia PQQ. All the animals (except those in normoxia) were exposed to simulated HH in a chamber at temperature 22°C ± 2°C, humidity 50% ± 5%, altitude 25,000 ft for 1, 3, or 7 days. After completion of the stipulated exposure time, gastrocnemius and soleus muscles were excised from animals for further analysis. Results: Greater lengths of hypoxic exposure caused progressively increased muscle ring finger-1 (MuRF-1; p  < 0.01) expression and calpain activation (0.56 ± 0.05 vs. 0.13 ± 0.02 and 0.44 ± 0.03 vs. 0.12 ± 0.021) by day 7, respectively in the gastrocnemius and soleus muscles. Myosin heavy chain type I (slow oxidative) fibers significantly ( p  > 0.01) decreased in gastrocnemius (>50%) and soleus (>46%) muscles by the seventh day of exposure. NCF supplementation showed ( p  ≤ 0.05) tremendous improvement in skeletal muscle acclimatization through effective alleviation of oxidative damage, and changes in calpain activity and atrophic markers at HA compared with hypoxia control or treatment alone with NC/PQQ. Conclusion: Thus, NCF-mediated anti-oxidative, anti-inflammatory effects lead to decreased proteolysis resulting in mitigated skeletal muscle atrophy under HH.

Differences in the food acquisition rates and in the energetic costs of metabolism seem to affect the growth rate variability of mussels. The aim of this study was to analyze if the physiological performances responsible for such growth rate variability are accompanied by structural differences at tissue or cellular level in the main organs involved in energy acquisition (gill) and processing (digestive gland). Fast growers had higher cilia density and metabolic efficiency in their gill, and well-developed digestive tissue with barely no connective tissue or atrophy. Slow-growing mussels displayed stress signs that impede the proper acquisition, digestion and absorption of food: low cilia density, low mitochondrial capacity and high antioxidant activity levels in the gills, and high atrophy of the digestive gland. The data herein explains the growth rate variability of mussels, demonstrating that morphological and functional differences exist between fast and slow growers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this study, the effect of resistance and endurance training with/without ursolic acid supplementation was evaluated to identify atrophy-related biomarkers in elderly rats induced by diabetes and a high-fat diet (HFD) based on in silico analysis algorithms and pharmaceutical methods. The visualizer software found differential gene expression levels in skeletal muscle atrophy via computed hub gene network parameters. Also, the impact of ursolic acid, as a potent inducer of the Trp53 protein in ameliorating decreased muscle mass, was analyzed in diabetic rats. Fifty-six-old male Wistar rats were randomly assigned into seven groups, including healthy control (Control), diabetic control (DM), Ursolic acid supplementation (UA), resistance training (RT), endurance training (ET), resistance training+ Ursolic acid supplementation (RT + U), and endurance training in combination with Ursolic acid supplementation (ET + U). Exercise intervention included 8 weeks of resistance or endurance training programs. Biomedical informatic outputs determined the P53 signaling pathway as a remarkable causative factor in the pathomechanism of atrophy. In addition, the results demonstrated that exercise and supplementation of UA impeded the interactions among p53/ATF4/p21. Moreover, ET and ursolic acid had a synergetic effect on the signaling pathway of p53/ATF4/p21 and probably could inhibit the aging process and modulate the p53/ATF4/p21 molecular pathway. The interaction between UA and endurance exercise significantly modified the activity of the p53/ATF4/p21 signaling pathway. Based on in silico studies, the p53/ATF4/p21 pathway plays an essential role in aging, and the inhibition of this pathway would be beneficial in decelerating the aging process. PRACTICAL APPLICATIONS: Ursolic acid (UA) is a natural pentacyclic triterpenoid carboxylic acid found in apples (a major compound of apple wax) and other fruits; it is known to improve skeletal muscle function and reduce the muscular atrophy pathways. We indicated that p53/ATF4/p21 signaling is an essential factor in aging, and the suppression of this pathway could be beneficial in the deceleration of the aging process. Therefore, this work would shed light on understanding the effect of exercise and nutrition interventions on preventing atrophy markers of skeletal muscle in diabetic rats. Further studies are needed to seek the precise mechanism of the synergism between UA and exercise in ameliorating atrophy markers., (© 2022 Wiley Periodicals LLC.)

Expression of FoxO transcription factors increases during certain forms of atrophy. In a dephosphorylated state, FoxOs participate in ubiquitin-mediated proteasomal degradation through the transcriptional activation of E3-ubiquitin ligases such as MAFbx/atrogin-1 and MuRF1. There is exhaustive research demonstrating that FoxO3a is sufficient to induce MAFbx/atrogin-1 and MuRF-1 expressions. In contrast, the data are conflicting on the requirement of FoxO1 signaling in the activation of the E3-ubiquitin ligases. Moreover, no reports currently exist on the particular role of FoxO1 in the molecular mechanisms involved in the progression of physiological muscle wasting. Here, we have applied the most extensively used rodent model of microgravity/functional unloading to stimulate disuse-induced skeletal muscle atrophy such as rat hindlimb suspension (HS). We showed that inhibition of FoxO1 activity by a selective inhibitor AS1842856 completely reversed an increase in expression of MuRF-1, but not MAFbx/atrogin-1, observed upon HS. Furthermore, we demonstrated that FoxO1 induced upregulation of another E3-ubiquitin-ligase of a MuRF protein family MuRF-2 in skeletal muscle subjected to disuse. Prevention of the MuRF increase upon HS impeded upregulation of transcript expression of a negative regulator of NFATc1 pathway calsarcin-2, which was associated with a partial reversion of MyHC-IId/x and MyHC-IIb mRNA expressions. Importantly, FoxO1 inhibition induced a marked increase in p70S6k phosphorylation, an important stage in the initiation of protein translation, concomitant with the restoration of global protein synthesis in the skeletal muscle of the HS rats. Examination of eIF3f expression and the eEF2k/eEF2 pathway, other factors controlling translation initiation and elongation respectively, did not reveal any impact of FoxO1 on their activity. Lastly, we observed a decrease in transcript levels of Sesn3, but not Sesn1 and Sesn2, upon disuse, which was completely reversed by FoxO1 inhibition. These data demonstrate that FoxO1 signaling contributes to the development of disuse-induced skeletal muscle atrophy, including slow to fast MyHC isoform shift, mostly through upregulation of MuRF-1 and MuRF-2 expression. Furthermore, FoxO1 inhibition is required to recover Sesn3 mRNA expression in atrophic conditions, which likely contributes to the enhanced p70S6k activity and restoration of the protein synthesis rate., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Skeletal muscle is an integral tissue system that plays a crucial role in the physical function of all vertebrates and is a key target for maintaining or improving health and performance across the lifespan. Based largely on cellular and animal models, there is some evidence that various forms of heat stress with or without resistance exercise may enhance skeletal muscle growth or reduce its loss. It is not clear whether these stimuli are similarly effective in humans or meaningful compared with exercise alone across various heating methodologies. Furthermore, the magnitude by which heat stress may influence whole body thermoregulatory responses and the connection to skeletal muscle adaptation remains ambiguous. Finally, the underlying mechanisms, which may include interaction between relevant heat shock proteins and intracellular hypertrophy and atrophy related factors, remain unclear. In this narrative review, we examine the relevant literature regarding heat stress alone or in combination with resistance exercise emphasizing skeletal muscle hypertrophy and atrophy across cellular and animal models, as well as human investigations. In addition, we present working mechanistic theories for heat shock protein-mediated signaling effects regarding hypertrophy and atrophy-related signaling processes. Importantly, continued research is necessary to determine the practical effects and mechanisms of heat stress with and without resistance exercise on skeletal muscle function via growth and maintenance.

The mineralocorticoid receptor (MR or NR3C2) is expressed in all types of cells from the different skin compartments. The binding and activation by glucocorticoids has a higher affinity than that on the closely related glucocorticoid receptor (GR or NR3C1). As both corticosteroid receptors are co-express in the skin and considering the therapeutic relevance of glucocorticoids to combat skin inflammatory diseases, it was proposed that several of the major side effects of topical glucocorticoids, such as skin atrophy and delayed wound healing, were due to unintended activation of the MR. Indeed, cutaneous MR blockade using genetic and pharmacological approaches in mice and human reduced corticosteroid-associated skin atrophy in conditions of endogenous and pharmacological glucocorticoid excess. Although data support the safety of topical MR antagonists combined with glucocorticoid, it is crucial to address the efficacy of treatment in skin inflammatory conditions and its impact on the overall metabolism. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc., (© 2021 The British Pharmacological Society.)

Egg-ceasing is a phenomenon that occurs in most avian species and significantly reduces productivity. Although several factors are reported to regulate the reproduction progress, the underlying molecular mechanism of egg-ceasing remains obscure. Herein, we identified and explored the differentially expressed miRNAs and mRNAs involved in ovarian atrophy via high throughput sequencing. We identified a total of 901 mRNAs and 50 miRNAs that were differentially expressed in egg-laying and atrophic ovaries. Among them, numerous differentially expressed gene (DEG) transcripts and target genes for miRNAs were significantly enriched in Gene Ontology terms such as reproductive processes, cell proliferation, and apoptosis pathways. In addition, an interaction network was constructed by considering target relationships and correlation of the expression levels between ovary development-related genes, miRNAs and pathways. We discovered mRNA and miRNAs transcripts that are candidate regulators of ovary development in egg-ceased geese. Our findings expanded our understanding of the functional of miRNAs in ovarian atrophy and demonstrated that RNA-Seq is a powerful tool for examining the molecular mechanism in regulating egg-ceasing., (Copyright © 2022 Elsevier Inc. All rights reserved.)