Tuberculosis during lung cancer treatment-A case series.

This study aimed to clarify the characteristics of patients with lung cancer undergoing treatment until the onset of tuberculosis. Between 2005 and 2019, patients who were admitted to Tokyo National Hospital due to tuberculosis during lung cancer treatment were examined retrospectively. There were 42 patients, and detailed medical information was obtained in 39 patients. The median age of the 39 patients were 75 years (range: 47-92 years), of which 33 were males and 36 were Japanese Baby Boomers or older. Regarding risk factors for developing tuberculosis, smoking was noted in 34 cases, oral corticosteroid use in 13, and previous tuberculosis in six. Thirty-seven patients had one risk factor and 19 had two or more risk factors, but diagnosis of latent tuberculosis infection (LTBI) was obtained in only one patients, and none had received LTBI treatment. The first-line treatment for lung cancer was resection in 13 cases, chemoradiotherapy in 6, chemotherapy in 10, radiation therapy in 3, laser therapy in 1, and best supportive care (BSC) alone in 6. At tuberculosis onset, BSC accounted for 17 cases, but other situations were considerably existed such as anticancer medication (12 cases), and observation after lung cancer treatment (10 cases). Tuberculosis occurred in various situations in elderly patients with lung cancer. It is critical to actively evaluate the risk of tuberculosis and consider LTBI screening and treatment.

IL-1RA in the supernatant of QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold Plus is useful for discriminating active tuberculosis from latent infection.

INTRODUCTION: The new-generation QuantiFERON (QFT)-TB Gold Plus (QFT-Plus) is expected to be useful because it includes a new peptide that is supposed to induce a CD8+ T cell response. There is a need for a new marker with sensitivity higher than that of the conventional IFN-γ release assays owing to false-negative results in the latter. This study aimed to compare cytokines in QFT-plus and QuantiFERON-Gold In-Tube (QFT-GIT) supernatants to discriminate between active tuberculosis and latent tuberculosis infection (LTBI). METHODS: A cross-sectional study was conducted at Tokyo National Hospital, wherein 21 LTBI patients and age and sex-matched active TB patients were randomly selected. The levels of various cytokines were measured and compared using the MAGPIX System, and receiver operating characteristic (ROC) curves were generated. RESULTS: IL-1RA, IFN-γ, CXCL10/IP-10, and CCL4/MIP-1ß levels were higher in the active TB group than in the LTBI group in QFT-GIT antigen (GIT Ag) tubes. In QFT-plus tubes, IL-1RA was higher in TB1 and TB2 tubes, while CCL2/MCP-1 was higher only in TB2 tubes. In Nil tubes, CCL5/RANTES, TNF-α, PDGF-BB, and IL-2 levels were significantly higher in the active TB group. IL-1RA in GIT Ag tubes showed the highest area under the curve of 0.8367. The sensitivity and specificity of IL-1RA were 66.7% (95% confidence interval [CI]: 43.0-85.4) and 90.5% (95% CI: 69.6-98.8), respectively, which were the highest among the cytokines. CONCLUSIONS: IL-1RA level in the QFT-GIT supernatant can be a good marker for discriminating active TB from LTBI.

Species identification, antifungal susceptibility, and clinical feature association of Aspergillus section Nigri isolates from the lower respiratory tract.

Species of Aspergillus section Nigri are generally identified by molecular genetics approaches, whereas in clinical practice, they are classified as A. niger by their morphological characteristics. This study aimed to investigate whether the species of Aspergillus section Nigri isolated from the respiratory tract vary depending on clinical diagnosis. Forty-four Aspergillus section Nigri isolates isolated from the lower respiratory tracts of 43 patients were collected from February 2012 to January 2017 at the National Hospital Organization (NHO) Tokyo National Hospital. Species identification was carried out based on ß-tubulin gene analysis. Drug susceptibility tests were performed according to the Clinical and Laboratory Standards Institute (CLSI) M38 3rd edition, and the clinical characteristics were retrospectively reviewed. A. welwitschiae was isolated most frequently, followed by A. tubingensis. More than half of the A. tubingensis isolates exhibited low susceptibility to azoles in contrast to only one A. welwitschiae isolate. Approximately three quarters of the patients from whom A. welwitschiae was isolated were diagnosed with colonization, whereas more than half the patients from whom A. tubingensis was isolated were diagnosed with chronic pulmonary aspergillosis (CPA). More attention needs to be given to the drug choice for patients with CPA with Aspergillus section Nigri infection because A. tubingensis, which was found to be frequently azole-resistant, was the most prevalent in these patients.

Comparison of QuantiFERON-TB Gold Plus, QuantiFERON-TB Gold In-Tube, and T-SPOT.TB among patients with tuberculosis.

OBJECTIVES: This study evaluated the efficacy of the following interferon (IFN)-γ release assays (IGRAs): QuantiFERON-TB Gold Plus (QFT-Plus), QFT-Gold In-Tube (QFT-GIT), and T-SPOT. TB (T-SPOT) with the quantitative values of IFN-γ response. METHODS: Blood samples were collected from patients with active tuberculosis (TB), latent TB infection (LTBI), individuals with previous TB infection, and healthy volunteers enrolled between May 2017 and June 2018. RESULTS: IGRAs results were analyzed in 175 subjects (76 had active TB, 14 had LTBI, 35 had prior TB infection, and 50 were healthy). QFT-Plus and QFT-GIT revealed equal efficacy for IFN-γ values, and the IFN-γ response in QFTs tended to increase with the spot counts in T-SPOT, with similar high sensitivities (approximately 90%) in the active TB group. The test concordance of two of three IGRAs was optimal among all subjects (κ coefficients: 0.82-0.96). Additionally, the median quantitative values of IFN-γ with QFT-Plus and QFT-GIT were higher in the active TB group than in the LTBI and previous TB groups. CONCLUSION: Three IGRAs showed equivalent efficacy with high sensitivities and higher IFN-γ response in active TB group than that in non-active TB group.

A case of Mycobacterium tuberculosis laboratory cross-contamination.

SETTING: A laboratory cross-contamination event was suspected because Mycobacterium tuberculosis was unexpectedly detected at a high incidence in the cultures of several clinical specimens at the National Hospital Organization, Tokyo National Hospital, Japan. OBJECTIVE: To describe a case of Mycobacterium tuberculosis laboratory cross-contamination. DESIGN: We reviewed the medical records of 20 patients whose clinical specimens were suspected to have been contaminated by Mycobacterium tuberculosis. Variable number of tandem repeat analysis with 15 loci, the Japan Anti-Tuberculosis Association-12, and three additional hyper-variable loci, was performed to identify the cross-contamination event. RESULTS: The clinical, laboratory, and variable number of tandem repeat data revealed that the cross-contamination had possibly originated from one strongly positive specimen, resulting in false-positive results in 11 other specimens, including a case treated with anti-tuberculosis drugs. CONCLUSION: Clinical and laboratory data must be re-evaluated when cross-contamination is suspected and variable number of tandem repeat analysis should be used to confirm cross-contamination. Furthermore, original isolates should be stored appropriately, without sub-culturing and genotyping should be performed at the earliest possible for better utilization of variable number of tandem repeat for the identification of cross-contamination.

[Retrospective Study of Clinical Features and Prognosis of Pneumococcal Pneumonia Among Patients Under 65 Years of Age].

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) for elderly people has been included in the National Immunization Program (NIP) of Japan since October 2014. Targets for PPSV23 were restricted to persons ≥65 years of age and persons 60 to 64 years of age with an underlying severe physical disability (expressed as 1st grade in Japan). In this study, the clinical courses of non-target persons <65 years of age were compared between those with non-severe underlying diseases (A group) and those without underlying diseases (B group), and the need to expand the targets for PPSV23 within the NIP was investigated. Persons with pneumococcal pneumonia who were diagnosed based on a positive sputum or blood culture result were enrolled between January 2004 and April 2014. As a result, the number of subjects in A group was 2.6 times larger than that in B group, and this difference was especially pronounced (4.2 times) among subjects between the age of 60 to 64 years. These findings suggest that persons with underlying disease without a 1st grade physical disability might also be susceptible to pneumococcal pneumonia. No significant differences in the severity of pneumonia, the length of treatment, or the rates of admission were seen between A group and B group. The severity of pneumonia and the rates of admission among targets of the NIP were significantly higher than those of A group. In conclusion, our study suggests that A group should also be included among the targets of the NIP and that all targets eligible to receive the pneumococcal vaccine within NIP should be inoculated.

[CLINICAL EFFECTS OF INTRAVENOUSLY ADMINISTERED LEVOFLOXACIN IN PATIENTS WITH PULMONARY TUBERCULOSIS: A RETROSPECTIVE STUDY].

OBJECTIVES: Our aim was to investigate the clini- cal effects of levofloxacin (LVFX) administered intravenously to patients with pulmonary tuberculosis. METHODS: We studied 65 patients hospitalized at The National Hospital Organization Tokyo National Hospital between January 2010 and December 2012. The patients did not have human immunodeficiency virus (HIV) infection, and received anti-tuberculous drugs intravenously due to the inability to receive drugs orally. RESULTS: Twenty-seven patients were intravenously treated with isoniazid (INH), streptomycin (SM) and LVFX (HLS), and 38 patients were treated with INH and SM (HS). For both groups, mean age was very high (80.6±15.0 years, HLS group; 81.0± 12.1 years, HS group) and serum albumin levels were low (2.0 ± 0.62 mg/dl and 2.1 ± 0.42 mg/dl, respectively). Most patients were administered oxygen (81.5%, HLS; 78.9 %, HS). In radiological findings, most patients had bilateral (92.6%, HLS; 92.1%, HS) and widely spread (55.6%, HLS; 57.9%, HS) shadows. No significant differences were found between both groups in terms of the above data, except for sex. Almost 70% of all patients died; 51.9% of patients in the HLS group and 50.0% of those in the HS group died of tuberculosis, while 18.5% of patients in the HLS group and 18.4% of those in the HS group died of the other diseases. There were no significant differences in the causes of death and the survival rates of both groups. CONCLUSION: Patients with pulmonary tuberculosis who were administered intravenous drugs were elderly and in poor general health. As such, mortality of these patients was very high. In this study, no clinical effects were found in the patients administered intravenous LVFX with INH and SM compared with patients treated with INH and SM.

Functions of miR-1 and miR-133a during the postnatal development of masseter and gastrocnemius muscles.

The present study investigated the function of miR-1 and miR-133a during the postnatal development of mouse skeletal muscles. The amounts of miR-1 and miR-133a were measured in mouse masseter and gastrocnemius muscles between 1 and 12 weeks after birth with real-time polymerase chain reaction and those of HDACs, MEF2, MyoD family, MCK, SRF, and Cyclin D1 were measured at 2 and 12 weeks with Western blotting. In both the masseter and gastrocnemius muscles, the amount of miR-1 increased between 1 and 12 weeks, whereas the amount of HADC4 decreased between 2 and 12 weeks. In the masseter muscle, those of MEF2, MyoD, Myogenin, and MCK increased between 2 and 12 weeks, whereas, in the gastrocnemius muscle, only those of MRF4 and MCK increased. The extent of these changes in the masseter muscle was greater than that in the gastrocnemius muscle. The amounts of miR-133a, SRF, and Cyclin D1 did not change significantly in the masseter muscle between 1 and 12 weeks after birth. By contrast, in the gastrocnemius muscle, the amounts of miR-133a and Cyclin D1 increased, whereas that of SRF decreased. Our findings suggest that the regulatory pathway of miR-1 via HDAC4 and MEF2 plays a more prominent role during postnatal development in the masseter muscle than in the gastrocnemius muscle, whereas that of miR-133a via SRF plays a more prominent role in the gastrocnemius muscle than in the masseter muscle.

Age-related changes in rat genioglossus, geniohyoid and masseter muscles.

OBJECTIVES: The aim of this study was to elucidate age-related changes from adult to middle age in the contractile properties of the masseter, genioglossus and geniohyoid muscles of the rat. MATERIALS AND METHODS: We analysed the expressions of myosin heavy chain (MyHC) mRNAs and proteins as indicators of the contractile properties in these muscles obtained from rats at 6, 12, 18 and 24 months of age using real-time PCR and SDS-PAGE. RESULTS: We found no marked age-related changes in the expressions of MyHC mRNAs and proteins in rat masseter and geniohyoid muscles, suggesting that the biological ageing process does not affect contractile properties in these muscles. However, we found a decrease in the expression of MyHC IIb mRNA with ageing in the rat genioglossus muscle, suggesting that biological ageing process induces at least some fast-to-slow myofibre phenotype transition. CONCLUSION: The biological ageing process from adult to middle age appears to differentially affect different types of craniofacial muscles.

Chronic Pulmonary Aspergillosis Caused by Aspergillus tubingensis Diagnosed by a Bronchoscopic Biopsy.

We herein report a case of chronic pulmonary aspergillosis (CPA) caused by Aspergillus tubingensis diagnosed by a bronchoscopic biopsy with negative serological and sputum culture findings. A 66-year-old man was referred for the assessment of a pulmonary cavity. Computed tomography showed a thick-walled cavity in the upper right pulmonary lobe. Serum ß-D glucan, Aspergillus galactomannan, and Aspergillus antibody tests were negative. Aspergillus species were not detected in the sputum. Culture and pathological specimens were obtained from the mass by bronchoscopy. Microscopic examination findings were consistent with Aspergillus niger complex morphologically and identified as Aspergillus tubingensis through DNA sequencing. The patient was diagnosed with chronic pulmonary aspergillosis.

Doctor's delay in endobronchial tuberculosis.

OBJECTIVE: The aim of this study was to investigate the current status of doctor's delay in diagnosing endobronchial tuberculosis (EBTB) and to elucidate the risk factors contributing to the delay. METHODS: Retrospective clinicopathological analysis. PATIENTS: Sixty-two patients with EBTB were admitted at our hospital between 1999 and 2010. Their backgrounds, symptoms, diagnoses at initial consultation, delay in diagnosis, and clinical examination results were analyzed. RESULTS: Of the 62 patients, 59 had acid-fast, bacillipositive sputum smear test results at admission. Among the 40 patients with total diagnostic delay of more than 2 months, only 11 experienced long patient's delay exceeding 2 months. However, 22 patients experienced long doctor's delay of more than 2 months (28% vs. 55%, respectively, p < 0.05), suggesting that doctor's delay contributes more to total delay than patient's delay. Fever was less frequent in patients with long doctor's delays than in those without (0% vs. 18%, respectively), at the initial consultation. In addition, radiographs showed that patients with long doctor's delays more frequently presented with shadows in the lower lung field (50% vs. 23%, p < 0.05), and most of these patients had noncavitary shadows on admission. All 7 patients diagnosed with bronchial asthma at the initial consultation had long doctor's delays. CONCLUSION: These findings demonstrate that long doctor's delays in diagnosing EBTB remain an issue. The clinical features of EBTB with long doctor's delays were confirmed to be quite different from those of pulmonary tuberculosis.

Association between the lack of teeth and the expression of myosins in masticatory muscles of microphthalmic mouse.

The purposes of the present study were to elucidate the influences of the deficiency of teeth on masticatory muscles, such as the masseter, temporalis and digastric muscles and compare the influence among masticatory muscles. We analysed the expressions of myosin heavy chain (MyHC) isoform messenger RNA (mRNA) and protein in these muscles in the microphthalmic (mi/mi) mouse, whose teeth cannot erupt because of a mutation in the mitf gene locus. The expression levels of MyHC mRNA and protein in the masseter, temporalis, digastric, tibialis anterior and gastrocnemius muscles of +/+ and mi/mi mice were analysed with real-time polymerase chain reaction and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively. The mi/mi masseter muscle at 8 weeks of age expressed 4.1-fold (p < 0.05) and 3.3-fold (p < 0.01) more MyHC neonatal mRNA and protein than that in the +/+, respectively; the expression level of MyHC neonatal protein was 19% of the total MyHC protein in the masseter muscle of mi/mi mice. In the digastric muscle, the expression levels of MyHC I mRNA and protein in the mi/mi mice were 4.7-fold (p < 0.05) and 5-fold (p < 0.01) higher than those in the +/+ mice. In the temporalis, tibialis anterior and gastrocnemius muscles, there was no significant difference in the expression levels of any MyHC isoform mRNA and protein between +/+ and mi/mi mice. These results indicate associations between the lack of teeth and the expression of MyHC in the masseter and digastric muscles but not such associations in the temporalis muscle, suggesting that the influence of tooth deficiency varies among the masticatory muscles.

IGF and myostatin pathways are respectively induced during the earlier and the later stages of skeletal muscle hypertrophy induced by clenbuterol, a ß2-adrenergic agonist.

Clenbuterol, a ß2-adrenergic agonist, increases the hypertrophy of skeletal muscle. Insulin-like growth factor (IGF) is reported to work as a potent positive regulator in the clenbuterol-induced hypertrophy of skeletal muscles. However, the precise regulatory mechanism for the hypertrophy of skeletal muscle induced by clenbuterol is unknown. Myostatin, a member of the TGFß super family, is a negative regulator of muscle growth. The aim of the present study is to elucidate the function of myostatin and IGF in the hypertrophy of rat masseter muscle induced by clenbuterol. To investigate the function of myostatin and IGF in regulatory mechanism for the clenbuterol-induced hypertrophy of skeletal muscles, we analysed the expression of myostatin and phosphorylation levels of myostatin and IGF signaling components in the masseter muscle of rat to which clenbuterol was orally administered for 21 days. Hypertrophy of the rat masseter muscle was induced between 3 and 14 days of oral administration of clenbuterol and was terminated at 21 days. The expression of myostatin and the phosphorylation of smad2/3 were elevated at 21 days. The phosphorylation of IGF receptor 1 (IGFR1) and akt1 was elevated at 3 and 7 days. These results suggest that myostatin functions as a negative regulator in the later stages in the hypertrophy of rat masseter muscle induced by clenbuterol, whereas IGF works as a positive regulator in the earlier stages.

A 73-year-old man with loss of consciousness during treatment for miliary tuberculosis.

Miliary tuberculosis is often associated with cerebral tuberculoma, which can manifest during treatment. We present images of a patient with cerebral tuberculoma detected due to emerging neurological symptoms during treatment of miliary tuberculosis.

Characteristics of outpatients with functional somatic syndromes at a university hospital's general medicine clinic.

Background: The term medically unexplained symptoms (MUS) is unhelpful for both patients and physicians, and more acceptable illness categories are needed as substitutes for MUS. While some potential substitutes are characterized by excessive psychological burden related to somatic symptoms, "functional somatic syndromes" (FSS) is a category that focuses on physical dysfunction and emphasizes similarities among individual syndromes. Examples of FSS include irritable bowel syndrome, functional dyspepsia, and fibromyalgia syndrome. This study aimed to distinguish FSS from MUS and compare the somatic and psychobehavioral characteristics of FSS with those of other diseases. Methods: This study included 1975 first-visit outpatients at a Japanese university hospital's general medicine clinic. According to their first-listed diagnosis, they were classified as having FSS, acute infection, organic disease (OD), psychiatric disorder, and unknown condition (UC). The somatic symptom burden and health-related quality of life (HRQoL) were assessed using the Somatic Symptom Scale-8 and EuroQol-5 Dimension, respectively; the involvement of psychobehavioral factors affecting somatic symptoms was also evaluated. Results: Overall, 33% of patients were included in the FSS category, and 93% of the supposed MUS (FSS and UC) were diagnosed with FSS. Compared with OD, FSS showed more severe somatic symptom burden, similar reduced HRQoL, and higher involvement of psychobehavioral factors. Conclusion: It can be useful to improve FSS diagnostic skills for the reduction of MUS misdiagnosis. Psychobehavioral factors might be less associated with MUS (in the narrow sense of the term) than FSS.

Impact of lung cancer surgery on comorbid Mycobacterium avium complex lung disease-A case series.

The number of cases with Mycobacterium avium and Mycobacterium intracellulare lung diseases (Mycobacterium avium complex lung disease [MACLD]) are increasing globally. Lung cancer can sometimes present as a comorbidity with MACLD; however, the clinical presentation and outcomes of comorbid MACLD following lung cancer resection remain unclear. Therefore, we retrospectively assessed 17 patients with MACLD undergoing lung cancer resection to determine the impact of lung cancer surgery on comorbid MACLD. Of the 17 patients, Mycobacterium avium and Mycobacterium intracellulare were present in 15 and 2 patients, respectively; 14 patients had stage I lung cancer and underwent lobectomy. Ten patients were postoperatively observed for MACLD without any further intervention, five patients underwent additional resection for conspicuous MACLD lesions, and the remaining two patients underwent complete resection for MACLD and lung cancer within the same lobe followed by rifampicin, ethambutol, and clarithromycin (RECAM) therapy. Seven patients exhibited postoperative MACLD exacerbation, six of whom developed exacerbation in the operated ipsilateral residual lobes. Six of these seven patients received RECAM, three of whom (43%) subsequently exhibited improvement. Attention should be paid to MACLD exacerbation during postoperative follow-up, especially in ipsilateral lobes. Although RECAM therapy may be beneficial in alleviating MACLD exacerbation, further investigation is warranted to validate these results.

Efficacy of acceptance and commitment therapy for people with type 2 diabetes: Systematic review and meta-analysis.

AIMS/INTRODUCTION: This systematic review and meta-analysis aimed to investigate the efficacy and safety of acceptance and commitment therapy (ACT) for people with type 2 diabetes mellitus. MATERIALS AND METHODS: Several electronic databases were examined on 16 January 2021, including PubMed, CENTRAL, PsycINFO, International Clinical Trials Registry Platform and ClinicalTrials.gov. Randomized controlled trials were included to compare ACT with usual treatment for people with type 2 diabetes reported in any language. Primary outcome measures were glycated hemoglobin, self-care ability assessed by the summary of diabetes self-care activities and all adverse events. The secondary outcome measure was acceptance assessed by the acceptance and action diabetes questionnaire. RESULTS: Of 678 publications initially identified, three trials were included in the meta-analysis. ACT resulted in a reduction in glycated hemoglobin (mean difference -0.62 points lower in the intervention group; 95% confidence interval -1.07 to -0.16; I2 = 0%; low-quality evidence). In addition, ACT increased the score of the summary of diabetes self-care activities (mean difference 8.48 points higher in the intervention group; 95% confidence interval 2.16-14.80; high-quality evidence). Adverse events were not measured in all trials. ACT increased scores of the acceptance and action diabetes questionnaire (mean difference 5.98 points higher in the intervention group; 95% confidence interval, 1.42-10.54; I2 = 43%; low-quality evidence). CONCLUSIONS: ACT might reduce glycated hemoglobin, and increase self-care ability and acceptance among people with type 2 diabetes.

Bone morphogenetic protein-2 functions as a negative regulator in the differentiation of myoblasts, but not as an inducer for the formations of cartilage and bone in mouse embryonic tongue.

BACKGROUND: In vitro studies using the myogenic cell line C2C12 demonstrate that bone morphogenetic protein-2 (BMP-2) converts the developmental pathway of C2C12 from a myogenic cell lineage to an osteoblastic cell lineage. Further, in vivo studies using null mutation mice demonstrate that BMPs inhibit the specification of the developmental fate of myogenic progenitor cells. However, the roles of BMPs in the phases of differentiation and maturation in skeletal muscles have yet to be determined. The present study attempts to define the function of BMP-2 in the final stage of differentiation of mouse tongue myoblast. RESULTS: Recombinant BMP-2 inhibited the expressions of markers for the differentiation of skeletal muscle cells, such as myogenin, muscle creatine kinase (MCK), and fast myosin heavy chain (fMyHC), whereas BMP-2 siRNA stimulated such markers. Neither the recombinant BMP-2 nor BMP-2 siRNA altered the expressions of markers for the formation of cartilage and bone, such as osteocalcin, alkaline phosphatase (ALP), collagen II, and collagen X. Further, no formation of cartilage and bone was observed in the recombinant BMP-2-treated tongues based on Alizarin red and Alcian blue stainings. Neither recombinant BMP-2 nor BMP-2 siRNA affected the expression of inhibitor of DNA binding/differentiation 1 (Id1). The ratios of chondrogenic and osteogenic markers relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH, a house keeping gene) were approximately 1000-fold lower than those of myogenic markers in the cultured tongue. CONCLUSIONS: BMP-2 functions as a negative regulator for the final differentiation of tongue myoblasts, but not as an inducer for the formation of cartilage and bone in cultured tongue, probably because the genes related to myogenesis are in an activation mode, while the genes related to chondrogenesis and osteogenesis are in a silencing mode.

Autophagic-lysosomal pathway functions in the masseter and tongue muscles in the klotho mouse, a mouse model for aging.

Klotho mutant (kl/kl) mice, a type of short-lived mouse models, display several aging-related phenotypes. To investigate whether the atrophy of skeletal muscles is induced in these mice via activation of the ubiquitin-proteasomal pathway and/or the autophagic-lysosomal pathway through an alteration of insulin/IGF-I signaling, we analyzed the activity of the two pathways for protein degradation and components of the insulin/IGF signaling pathway in their skeletal muscles. The masseter, tongue, and gastrocnemius muscles in kl/kl showed marked reductions in muscle weight and in myofiber diameter compared with +/+. The autophagic-lysosomal pathway in kl/kl was activated in the masseter and tongue, but not in the gastrocnemius, compared with that in +/+, whereas the ubiquitin-proteasomal pathway in these three muscles of kl/kl was not altered. No marked difference in the phosphorylation levels of insulin/IGF-I signaling components, such as insulin/IGF-I receptor, Akt, and FoxO in three muscles studied were found between kl/kl and +/+, but the phosphorylation levels of signaling component at the downstream of mTOR such as 4E-BP1 and p70 S6K were suppressed in the masseter and tongue of kl/kl compared with +/+. Deficiency of essential amino acids is reported to activate the autophagy-lysosomal pathway through the down-regulation of mTOR, not through IGF-Akt-FoxO. The masseter and tongue seem to be more actively moved than limb muscles in kl/kl, because they are essential for survival activities such as mastication, swallowing, and respiration. Thus, the deficiency of amino acid by the active movement of the masseter and tongue seems to stimulate the autophagic-lysosomal pathway via the down-regulation of mTOR signalling pathway.