Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

Drug-related sarcopenia as a secondary sarcopenia.

Sarcopenia has a significant impact on falls, physical function, activities of daily living, and quality of life in older adults, and its prevention and treatment are becoming increasingly important as the global population ages. In addition to primary age-related sarcopenia, activity-related sarcopenia, disease-related sarcopenia, and nutrition-related sarcopenia have been proposed as secondary sarcopenia. Polypharmacy and potentially inappropriate medication based on multiple diseases cause health problems in older patients. In some cases, drugs used for therapeutic or preventive purposes act on skeletal muscle as adverse drug reactions and induce sarcopenia. Although sarcopenia caused by these adverse drug reactions may be more common in older patients, in particular those taking many medications, drug-related sarcopenia has not yet received much attention. This review summarizes drugs that may induce sarcopenia and emphasizes the importance of drug-related sarcopenia as a secondary sarcopenia. Geriatr Gerontol Int 2024; 24: 195-203.

The association between early rehabilitation and ambulatory ability at discharge in patients with hip fractures at acute-phase rehabilitation wards: a survey of the Japan Association of Rehabilitation Database.

This study aimed to examine the effectiveness of early rehabilitation in patients with femoral neck fractures admitted to acute care settings in Japan using the data registered with the Japan Association of Rehabilitation Databases (JARD). We included data for 401 patients (out of 3088 patients) aged ≥ 65 years (85 males, 316 females) from nine hospitals who sustained a femoral neck fracture between July 2005 and September 2015. Using the number of days until surgery or the number of days until the start of rehabilitation or both as the explanatory variables, and the indoor mobility at discharge as the outcome variable, we calculated the adjusted rate ratio (ARR) and 95% confidence interval (CI) using Poisson regression analysis (age, sex, cognitive impairment, concurrent symptoms, and previous history of fracture adjusted as covariates). The ARR for independent walking at the discharge of the early-rehabilitation group (starting rehabilitation within two days after the injury) was significantly higher (ARR: 2.01, 95% CI: 1.34-3.02) than that of the non-early rehabilitation group. These results suggest that early acute-phase rehabilitation after a femoral neck fracture in older patients allows for better ambulatory ability at discharge, regardless of the time to surgery.

Cathepsin S activity controls chronic stress-induced muscle atrophy and dysfunction in mice.

Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important role in human pathobiology. Given that cathepsin S (CTSS) is upregulated in the stressed vascular and adipose tissues, we investigated whether CTSS participates in chronic stress-induced skeletal muscle mass loss and dysfunction, with a special focus on muscle protein metabolic imbalance and apoptosis. Eight-week-old male wildtype (CTSS+/+) and CTSS-knockout (CTSS-/-) mice were randomly assigned to non-stress and variable-stress groups. CTSS+/+ stressed mice showed significant losses of muscle mass, dysfunction, and fiber area, plus significant mitochondrial damage. In this setting, stressed muscle in CTSS+/+ mice presented harmful alterations in the levels of insulin receptor substrate 2 protein content (IRS-2), phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, and phospho-mammalian target of rapamycin, forkhead box-1, muscle RING-finger protein-1 protein, mitochondrial biogenesis-related peroxisome proliferator-activated receptor-γ coactivator-α, and apoptosis-related B-cell lymphoma 2 and cleaved caspase-3; these alterations were prevented by CTSS deletion. Pharmacological CTSS inhibition mimics its genetic deficiency-mediated muscle benefits. In C2C12 cells, CTSS silencing prevented stressed serum- and oxidative stress-induced IRS-2 protein reduction, loss of the myotube myosin heavy chain content, and apoptosis accompanied by a rectification of investigated molecular harmful changes; these changes were accelerated by CTSS overexpression. These findings demonstrated that CTSS plays a role in IRS-2-related protein anabolism and catabolism and cell apoptosis in stress-induced muscle wasting, suggesting a novel therapeutic strategy for the control of chronic stress-related muscle disease in mice under our experimental conditions by regulating CTSS activity.

Cathepsin S deficiency improves muscle mass loss and dysfunction via the modulation of protein metabolism in mice under pathological stress conditions.

Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non-enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress-related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight-week-old male wildtype (CTSS+/+ ) and CTSS-knockout (CTSS-/- ) mice were randomly assigned to non-stress and variable-stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non-stressed mice, stressed CTSS+/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress-induced harmful changes in the levels of oxidative stress-related (gp91phox and p22phox ,), inflammation-related (SDF-1, CXCR4, IL-1ß, TNF-α, MCP-1, ICAM-1, and VCAM-1), mitochondrial biogenesis-related (PPAR-γ and PGC-1α) genes and/or proteins and protein metabolism-related (p-PI3K, p-Akt, p-FoxO3α, MuRF-1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS-/- mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress-related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress-related muscular diseases.

Effect of drugs on nutritional status and drug-nutrition interactions in older patients.

Older patients are prone to multimorbidity or related polypharmacy, which may cause various adverse drug reactions (ADRs) and a high incidence of drug-related health problems. Although not often noted, ADRs include nutrition-related adverse reactions. Aging, multiple illnesses, mental and psychological problems, declining physical function, and environmental factors can lead to decreased food intake and increased metabolic stress in older people, resulting in energy imbalances that cause malnutrition. ADRs can lead to appetite loss, followed by decreased food intake, which in turn causes malnutrition and deficiencies of various nutrients. However, these nutrition-related ADRs have received less attention. This review article describes drug-nutrition interactions, with a particular focus on older patients. Geriatr Gerontol Int 2023; 23: 465-477.

CTSS Modulates Stress-Related Carotid Artery Thrombosis in a Mouse FeCl3 Model.

BACKGROUND: Exposure to chronic psychological stress is a risk factor for metabolic cardiovascular disease. Given the important role of lysosomal CTSS (cathepsin S) in human pathobiology, we examined the role of CTSS in stress-related thrombosis, focusing on inflammation, oxidative stress, and apoptosis. METHODS: Six-week-old wild-type mice (CTSS+/+) and CTSS-deficient mice (CTSS-/-) randomly assigned to nonstress and 2-week immobilization stress groups underwent iron chloride3 (FeCl3)-induced carotid thrombosis surgery for morphological and biochemical studies. RESULTS: On day 14 poststress/surgery, stress had increased the lengths and weights of thrombi in the CTSS+/+ mice, plus harmful changes in the levels of PAI-1 (plasminogen activation inhibitor-1), ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 13 motifs), and vWF (von Willebrand factor) and arterial tissue CTSS expression. Compared to the nonstressed CTSS+/+ mice, the stressed CTSS-/- mice had decreased levels of PAI-1, vWF, TNF (tumor necrosis factor)-α, interleukin-1ß, toll-like receptor-4, cleaved-caspase 3, cytochrome c, p16INK4A, gp91phox, p22phox, ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein-1), MyD88 (myeloid differentiation primary response 88), and MMP (matrix metalloproteinase)-2/-9 and increased levels of ADAMTS13, SOD (superoxide dismutase)-1/-2, eNOS (endothelial NO synthase), p-Akt (phospho-protein kinase B), Bcl-2 (B-cell lymphoma-2), p-GSK3α/ß (phospho-glycogen synthase kinases alpha and beta), and p-Erk1/2 (phospho-extracellular signal-regulated kinase 1 and 2) mRNAs and/or proteins. CTSS deletion also reduced the arterial thrombus area and endothelial loss. A pharmacological inhibition of CTSS exerted a vasculoprotective action. In vitro, CTSS silencing and overexpression, respectively, reduced and increased the stressed serum and oxidative stress-induced apoptosis of human umbilical vein endothelial cells, and they altered apoptosis-related proteins. CONCLUSIONS: CTSS inhibition appeared to improve the stress-related thrombosis in mice that underwent FeCl3-induction surgery, possibly by reducing vascular inflammation, oxidative stress, and apoptosis. CTSS could thus become a candidate therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disease.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

Total pain in advanced dementia: a quick literature review.

Objective: This quick literature review aimed to organize information on the detailed components of total pain in older people with advanced dementia in a holistic manner. Materials and Methods: The authors analyzed qualitative data from relevant clinical guidelines or textbooks, focusing on certain types of pain and distress in older people with advanced dementia, followed by an expert panel review by research team members. In the search, the authors defined a person with advanced dementia as having a functional assessment staging tool scale score greater than or equal to six. Results: The model covered a wide variety of pain, from physical pain to dementia-related psychological and spiritual aspects of total pain, including living environment change, stigma, discrimination, lack of communication and understanding, loss of sense of control and dignity, and cultural distress. It also identified physical appearance as an important factor in dying with dignity, as established by existing research on individuals with incurable cancers. Conclusion: The conceptual model of total pain in people with advanced dementia is expected to help turn healthcare professionals' attention to physical, psychological, social, and spiritual contributors to total pain in advanced dementia.

Nutritional Management of Sarcopenia and Frailty-Shift from Metabolic Syndrome to Frailty.

Older adults have physical and metabolic characteristics, and there are many differences in nutritional outcomes from middle-aged adults. In addition, there are many factors that cause malnutrition peculiar to the older adults, which are not seen in middle-aged adults, and it is easy for them to lose weight and become malnourished. Therefore, nutritional management needs to take into account the age of each subject. Uniform nutritional management can even cause poor health outcomes. The concept of frailty, especially phenotype frailty, and sarcopenia, which have been advocated with the aging of the population and the extension of life expectancy around the world, is very important in considering the extension of healthy life expectancy. In other words, in the super-aged society, frailty and sarcopenia have been emphasized as factors of functional decline, physical dysfunction, and the need for long-term care in addition to the well-known diseases such as cardiovascular disease, malignant tumors, and infectious disease. In fact, these two conditions are strongly associated with the increased risk of new disease development, falls, fractures, disability, hospitalization and death in the older adults. These two conditions are primarily associated with malnutrition and decreased dietary protein intake, and may recover to robustness again with appropriate interventions such as nutritional therapy. Therefore, undernutrition measures are more important for prevention of frailty and sarcopenia than measures for obesity against metabolic syndrome in the older adults, especially in the late-stage older people.

Young bone marrow transplantation prevents aging-related muscle atrophy in a senescence-accelerated mouse prone 10 model.

BACKGROUND: Young bone marrow transplantation (YBMT) has been shown to stimulate vascular regeneration in pathological conditions, including ageing. Here, we investigated the benefits and mechanisms of the preventive effects of YBMT on loss of muscle mass and function in a senescence-associated mouse prone 10 (SAMP10) model, with a special focus on the role of growth differentiation factor 11 (GDF-11). METHODS: Nine-week-old male SAMP10 mice were randomly assigned to a non-YBMT group (n = 6) and a YBMT group (n = 7) that received the bone marrow of 8-week-old C57BL/6 mice. RESULTS: Compared to the non-YBMT mice, the YBMT mice showed the following significant increases (all P < 0.05 in 6-7 mice): endurance capacity (>61.3%); grip strength (>37.9%), percentage of slow myosin heavy chain fibres (>14.9-15.9%). The YBMT also increased the amounts of proteins or mRNAs for insulin receptor substrate 1, p-Akt, p-extracellular signal-regulated protein kinase1/2, p-mammalian target of rapamycin, Bcl-2, peroxisom proliferator-activated receptor-γ coactivator (PGC-1α), plus cytochrome c oxidase IV and the numbers of proliferating cells (n = 5-7, P < 0.05) and CD34+/integrin-α7+ muscle stem cells (n = 5-6, P < 0.05). The YMBT significantly decreased the levels of gp91phox, caspase-9 proteins and apoptotic cells (n = 5-7, P < 0.05) in both muscles; these beneficial changes were diminished by the blocking of GDF-11 (n = 5-6, P < 0.05). An administration of mouse recombinant GDF-11 improved the YBMT-mediated muscle benefits (n = 5-6, P < 0.05). Cell therapy with young bone marrow from green fluorescent protein (GFP) transgenic mice exhibited GFP+ myofibres in aged muscle tissues. CONCLUSIONS: These findings suggest that YBMT can prevent muscle wasting and dysfunction by mitigating apoptosis and proliferation via a modulation of GDF-11 signalling and mitochondrial dysfunction in SAMP10 mice.

Human umbilical cord-derived mesenchymal stromal cells ameliorate aging-associated skeletal muscle atrophy and dysfunction by modulating apoptosis and mitochondrial damage in SAMP10 mice.

BACKGROUND: Skeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease. METHODS AND RESULTS: We investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34+/Integrin α7+ cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs. CONCLUSIONS: Our results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases.

Cathepsin K Deficiency Prevented Kidney Damage and Dysfunction in Response to 5/6 Nephrectomy Injury in Mice With or Without Chronic Stress.

BACKGROUND: Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress. METHODS: Male 7-week-old WT (wild type; CatK+/+) and CatK-deficient (CatK-/-) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation. RESULTS: Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22phox, gp91phox, CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy-related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK's involvement in PPAR-γ/caspase-8-mediated cell apoptosis in response to superoxide and stressed serum. CONCLUSIONS: These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.

Potentially inappropriate medications increase while prevalence of polypharmacy/hyperpolypharmacy decreases in Japan: A comparison of nationwide prescribing data.

BACKGROUND: To elucidate recent prescription trends for older adults and the background underlying changes over time with a particular focus on the prevalence of polypharmacy and potentially inappropriate medications (PIMs). METHODS: We cross-sectionally collected prescription data of patients aged ≧65 years who visited chain pharmacies dispensing prescribed drugs from all types of outpatient settings for one month in two sampling periods (October, 2014 and December, 2019), and the data were analysed. Prevalence of polypharmacy and factors associated with PIMs between the two periods were investigated. RESULTS: The average number of drugs prescribed decreased over time (4.05 ± 3.24 in 2014 vs. 3.98 ± 3.16 in 2019, p < 0.001), as did the prevalence of polypharmacy (50.1% in 2014 vs. 48.2% in 2019, p < 0.001). Meanwhile, the prevalence of PIMs exhibited a marked increase (overall: 26.8% in 2014 vs. 43.7% in 2019, aged 65-74: 25.6% in 2014 vs. 40.3% in 2019, aged 75-84: 27.4% in 2014 vs. 43.9% in 2019), which was the most pronounced in patients aged over 85 (29.4% in 2014 vs. 53.0% in 2019). The number of classes of drugs positively associated with PIMs in 2019 increased from that in 2014. The increasing trend was most prominently observed in the oldest age category (over 85 years, 2 in 2014 vs. 6 in 2019). CONCLUSIONS: The comparison of monthly prescribing data with an interval of 5 years suggested an increasing trend in the prevalence of PIMs, contrary to the declining prevalence of polypharmacy.

A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency.

Werner syndrome (WS) is a progeroid syndrome caused by mutations in the WRN gene, which encodes the RecQ type DNA helicase for the unwinding of unusual DNA structures and is implicated in DNA replication, DNA repair, and telomere maintenance. patients with WS are prone to develop malignant neoplasms, including hematological malignancies. However, the pathogenesis of WS-associated hematological malignancies remains uncharacterized. Here we investigated the somatic gene mutations in WS-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Whole-exome sequencing (WES) of 4 patients with WS with MDS/AML revealed that all patients had somatic mutations in TP53 but no other recurrent mutations in MDS/AML. TP53 mutations were identified at low allele frequencies at more than one year before the MDS/AML stage. All 4 patients had complex chromosomal abnormalities including those that involved TP53. Targeted sequencing of nine patients with WS without apparent blood abnormalities did not detect recurrent mutations in MDS/AML except for a PPM1D mutation. These results suggest that patients with WS are apt to acquire TP53 mutations and/or chromosomal abnormalities involving TP53, rather than other MDS/AML-related mutations. TP53 mutations are frequently associated with prior exposure to chemotherapy; however, all four patients with WS with TP53 mutations/deletions had not received any prior chemotherapy, suggesting a pathogenic link between WRN mutations and p53 insufficiency. These results indicate that WS hematopoietic stem cells with WRN insufficiency acquire competitive fitness by inactivating p53, which may cause complex chromosomal abnormalities and the subsequent development of myeloid malignancies. These findings promote our understanding of the pathogenesis of myeloid malignancies associated with progeria.

Cathepsin K activity controls cachexia-induced muscle atrophy via the modulation of IRS1 ubiquitination.

BACKGROUND: Cachexia is a complicated metabolic disorder that is characterize by progressive atrophy of skeletal muscle. Cathepsin K (CTSK) is a widely expressed cysteine protease that has garnered attention because of its enzymatic and non-enzymatic functions in signalling in various pathological conditions. Here, we examined whether CTSK participates in cancer-induced skeletal muscle loss and dysfunction, focusing on protein metabolic imbalance. METHODS: Male 9-week-old wild-type (CTSK+/+ , n = 10) and CTSK-knockout (CTSK-/- , n = 10) mice were injected subcutaneously with Lewis lung carcinoma cells (LLC; 5 × 105 ) or saline, respectively. The mice were then subjected to muscle mass and muscle function measurements. HE staining, immunostaining, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting were used to explore the CTSK expression and IRS1/Akt pathway in the gastrocnemius muscle at various time points. In vitro measurements included CTSK expression, IRS1/Akt pathway-related target molecule expressions, and the diameter of C2C12 myotubes with or without LLC-conditioned medium (LCM). An IRS1 ubiquitin assay, and truncation, co-immunoprecipitation, and co-localization experiments were also performed. RESULTS: CTSK+/+ cachectic animals exhibited loss of skeletal muscle mass (muscle weight loss of 15%, n = 10, P < 0.01), muscle dysfunction (grip strength loss > 15%, n = 10, P < 0.01), and fibre area (average area reduction > 30%, n = 5, P < 0.01). Compared with that of non-cachectic CTSK+/+ mice, the skeletal muscle of cachectic CTSK+/+ mice exhibited greater degradation of insulin receptor substrate 1 (IRS1, P < 0.01). In this setting, cachectic muscles exhibited decreases in the phosphorylation levels of protein kinase B (Akt308 , P < 0.01; Akt473 , P < 0.05) and anabolic-related proteins (the mammalian target of rapamycin, P < 0.01) and increased levels of catabolism-related proteins (muscle RING-finger protein-1, P < 0.01; MAFbx1, P < 0.01) in CTSK+/+ mice (n = 3). Although there was no difference in LLC tumour growth (n = 10, P = 0.44), CTSK deletion mitigated the IRS1 degradation, loss of the skeletal muscle mass (n = 10, P < 0.01), and dysfunction (n = 10, P < 0.01). In vitro, CTSK silencing prevented the IRS1 ubiquitination and loss of the myotube myosin heavy chain content (P < 0.01) induced by LCM, and these changes were accelerated by CTSK overexpression even without LCM. Immunoprecipitation showed that CTSK selectively acted on IRS1 in the region of amino acids 268 to 574. The results of co-transfection of IRS1-N-FLAG or IRS1-C-FLAG with CTSK suggested that CTSK selectively cleaves IRS1 and causes ubiquitination-related degradation of IRS1. CONCLUSIONS: These results demonstrate that CTSK plays a novel role in IRS1 ubiquitination in LLC-induced muscle wasting, and suggest that CTSK could be an effective therapeutic target for cancer-related cachexia.

Proliferin-1 Ameliorates Cardiotoxin-Related Skeletal Muscle Repair in Mice.

BACKGROUND: We recently demonstrated that proliferin-1 (PLF-1) functions as an apoptotic cell-derived growth factor and plays an important role in vascular pathobiology. We therefore investigated its role in muscle regeneration in response to cardiotoxin injury. METHODS AND RESULTS: To determine the effects of PLF-1 on muscle regeneration, we used a CTX-induced skeletal muscle injury model in 9-week-old male mice that were administered with the recombinant PLF-1 (rPLF-1) or neutralizing PLF-1 antibody. The injured muscles exhibited increased levels of PLF-1 gene expression in a time-dependent manner. On day 14 after injury, rPLF-1 supplementation ameliorated CTX-induced alterations in muscle fiber size, interstitial fibrosis, muscle regeneration capacity, and muscle performance. On day 3 postinjury, rPLF-1 increased the levels of proteins or genes for p-Akt, p-mTOR, p-GSK3α/ß, p-Erk1/2, p-p38MAPK, interleukin-10, Pax7, MyoD, and Cyclin B1, and it increased the numbers of CD34+/integrin-α7+ muscle stem cells and proliferating cells in the muscles and/or bone marrow of CTX mice. An enzyme-linked immunosorbent assay revealed that rPLF-1 suppressed the levels of plasma tumor necrosis factor-α and interleukin-1ß in CTX mice. PLF-1 blocking accelerated CTX-related muscle damage and dysfunction. In C2C12 myoblasts, rPLF-1 increased the levels of proteins for p-Akt, p-mTOR, p-GSK3α/ß, p-Erk1/2, and p-p38MAPK as well as cellular functions; and these effects were diminished by the depletion of PLF-1 or silencing of its mannose-6-phosphate receptor. CONCLUSIONS: These findings demonstrated that PLF-1 can improve skeletal muscle repair in response to injury, possibly via the modulation of inflammation and proliferation and regeneration, suggesting a novel therapeutic strategy for the management of skeletal muscle diseases.

Associations Between Polypharmacy and Gait Speed According to Cognitive Impairment Status: Cross-Sectional Study in a Japanese Memory Clinic.

BACKGROUND: Polypharmacy, usually defined as the use of 5 or more drugs, is associated with reduced quality of life, adverse events, and frailty. Slow gait speed is a component of physical frailty, and some studies have suggested an association between polypharmacy and slow gait speed. OBJECTIVE: We aimed to determine the effects of polypharmacy on the gait difference according to stages of cognitive decline in a cross-sectional study of memory clinic patients. METHODS: Participants were 431 outpatients aged 65 year or older who were cognitively normal (CN) or had mild cognitive impairment (MCI) or dementia due to Alzheimer's disease. Participants were divided into a polypharmacy group and a non-polypharmacy group in each group. Multiple regression analysis and logistic analysis were used for data analysis. RESULTS: There were 182 patients in the polypharmacy group and 249 patients in the non-polypharmacy group. Multiple regression analysis revealed that gait speed had significant negative associations with number of medications and polypharmacy status in the CN group (ß: -0.026 [-0.041 to -0.0018] and -0.128 [-0.022 to -0.0033], respectively) and MCI group (-0.018 [-0.028 to -0.0009] and -0.100 [-0.166 to -0.0034]). Logistic regression analysis also showed that number of medications was associated with slow gait status (< 1 m/s) in the CN group (OR: 1.336 [1.115 to 1.601]) and MCI group (1.128 [1.022 to 1.244]). CONCLUSION: CN and MCI patients with polypharmacy have slower gait speed. Attention should be paid to decreased gait speed in older adults with polypharmacy even when their cognitive function is relatively preserved.

Management guideline for Werner syndrome 2020. 7. Skin ulcer associated with Werner syndrome: Dermatological treatment.

Skin ulcers in Werner's syndrome often arise from hyperkeratotic lesions and trauma to pressure points such as the plantar region, and are more difficult to treat than wound healing in healthy individuals. Multiple factors contribute to the intractable skin ulcers in Werner's syndrome, including skin thinning, sclerosis, fatty tissue loss, impaired blood flow, calcification, and excessive pressure due to osteoarticular deformity. Treatment includes topical application of a keratolytic agent for keratosis around the ulcer. Treatment of ulcers is the same as for normal ulcers, and if the ulcer is associated with infection and necrotic tissue, surgical debridement with a scalpel or scissors should be performed as much as possible after washing with saline or mildly warm water or with an antibacterial agent. Topical medications that promote softening and debridement of the necrotic tissue are used with careful control of moisture in the wound. Topical agents that promote granulation should be used in wounds where necrotic tissue has been removed without infection. Dressings to maintain a moist environment in the wound may also be useful. If the wound does not improve with conservative treatment, surgical treatment should be considered. Geriatr Gerontol Int 2021; 21: 160-162.