Optimization of Xenografting Methods for Generating Human Skeletal Muscle in Mice.

Xenografts of human skeletal muscle generated in mice can be used to study muscle pathology and to test drugs designed to treat myopathies and muscular dystrophies for their efficacy and specificity in human tissue. We previously developed methods to generate mature human skeletal muscles in immunocompromised mice starting with human myogenic precursor cells (hMPCs) from healthy individuals and individuals with facioscapulohumeral muscular dystrophy (FSHD). Here, we examine a series of alternative treatments at each stage in order to optimize engraftment. We show that (i) X-irradiation at 25Gy is optimal in preventing regeneration of murine muscle while supporting robust engraftment and the formation of human fibers without significant murine contamination; (ii) hMPC lines differ in their capacity to engraft; (iii) some hMPC lines yield grafts that respond better to intermittent neuromuscular electrical stimulation (iNMES) than others; (iv) some lines engraft better in male than in female mice; (v) coinjection of hMPCs with laminin, gelatin, Matrigel, or Growdex does not improve engraftment; (vi) BaCl2 is an acceptable replacement for cardiotoxin, but other snake venom preparations and toxins, including the major component of cardiotoxin, cytotoxin 5, are not; and (vii) generating grafts in both hindlimbs followed by iNMES of each limb yields more robust grafts than housing mice in cages with running wheels. Our results suggest that replacing cardiotoxin with BaCl2 and engrafting both tibialis anterior muscles generates robust grafts of adult human muscle tissue in mice.

Myosteatosis and aortic calcium score on abdominal CT as prognostic markers in non-dialysis chronic kidney disease patients.

We aimed to examine the relationship between abdominal computed tomography (CT)-based body composition data and both renal function decline and all-cause mortality in patients with non-dialysis chronic kidney disease (CKD). This retrospective study comprised non-dialysis CKD patients who underwent consecutive unenhanced abdominal CT between January 2010 and December 2011. CT-based body composition was measured using semiautomated method that included visceral fat, subcutaneous fat, skeletal muscle area and density, and abdominal aortic calcium score (AAS). Sarcopenia and myosteatosis were defined by decreased skeletal muscle index (SMI) and decreased skeletal muscle density, respectively, each with specific cutoffs. Risk factors for CKD progression and survival were identified using logistic regression and Cox proportional hazard regression models. Survival between groups based on myosteatosis and AAS was compared using the Kaplan-Meier curve. 149 patients (median age: 70 years) were included; 79 (53.0%) patients had sarcopenia and 112 (75.2%) had myosteatosis. The median AAS was 560.9 (interquartile range: 55.7-1478.3)/m2. The prognostic factors for CKD progression were myosteatosis [odds ratio (OR) = 4.31, p = 0.013] and high AAS (OR = 1.03, p = 0.001). Skeletal muscle density [hazard ratio (HR) = 0.93, p = 0.004] or myosteatosis (HR = 4.87, p = 0.032) and high AAS (HR = 1.02, p = 0.001) were independent factors for poor survival outcomes. The presence of myosteatosis and the high burden of aortic calcium were significant factors for CKD progression and survival in patients with non-dialysis CKD.

[Current and Future Status of Muscle Pathology: The Position of Muscle Pathology Diagnosis in the Future].

Many muscle disease names are mostly based on muscle pathology findings. Naturally, muscle pathology is important in the diagnosis of muscle diseases. Moreover, in recent years, extensive genetic analysis and autoantibody testing for myositis have been applied clinically, although muscle biopsies are less performed. However, muscle pathology should be proactively considered when a single gene presents multiple phenotypes, when variants of unknown pathological significance are detected, or in cases of autoimmune myositis that may be misdiagnosed as muscular dystrophy.

Pathological findings with vacuoles in anti-mitochondrial antibody-positive inflammatory myopathy.

BACKGROUND: A few patients with inflammatory myopathy showed anti-mitochondrial antibody (AMA) positivity. This study aimed to report the clinical and pathological findings with vacuoles in 3 cases of such patients. METHODS: Three cases with myositis from the Myositis Clinical Database of Peking University First Hospital were identified with AMA positivity. Their clinical records were retrospectively reviewed and the data was extracted. All the 3 cases underwent muscle biopsy. RESULTS: Three middle-aged patients presented with chronic-onset weakness of proximal limbs, marked elevation of creatine kinase, and AMA-positivity. Two of the 3 cases meet the criteria of primary biliary cholangitis. All the 3 cases presented with cardiac involvement and proteinuria. Two cases developed type 2 respiratory failure. MRI of the thigh muscle showed multiple patches of edema bilaterally in both cases, mostly in the adductor magnus. Pathological findings include degeneration of muscle fibers, diffused MHC-I positivity, and complement deposits on cell membranes. Vacuoles without rims of different sizes were discovered under the membrane of the muscle fibers. A few RBFs were discovered in case 1, while a diffused proliferation of endomysium and perimysium was shown in case 2. CONCLUSIONS: AMA-positive inflammatory myopathy is a disease that could affect multiple systems. Apart from inflammatory changes, the pathological findings of muscle can also present vacuoles.

Bilateral hibernomas in the femoral regions of a dog.

A 14-year-old intact male Chihuahua dog was presented with masses located between the biceps femoris and adductor muscles in both hind limbs. Based on histopathological, immunohistochemical, and ultrastructural findings, we diagnosed these masses as bilateral hibernomas in the femoral regions. The dog had no evidence of recurrence or metastasis of the hibernomas through a 4-month postoperative follow-up. This is apparently the first report of bilateral hibernomas in the femoral regions of a dog. Key clinical message: Bilateral hibernomas should be considered as a differential diagnosis for masses occurring in the femoral regions of dogs.

Hibernomes bilatéraux dans les régions fémorales d'un chien. Un chien Chihuahua mâle intact de 14 ans a été présenté avec des masses situées entre le biceps fémoral et les muscles adducteurs des deux membres postérieurs. Sur la base des résultats histopathologiques, immunohistochimiques et ultrastructuraux, nous avons diagnostiqué ces masses comme des hibernomes bilatéraux dans les régions fémorales. Le chien n'avait aucun signe de récidive ou de métastases des hibernomes au cours d'un suivi postopératoire de 4 mois. Il s'agit apparemment du premier rapport d'hibernome bilatéral dans les régions fémorales d'un chien.Message clinique clé:Les hibernomes bilatéraux doivent être considérés comme un diagnostic différentiel pour les masses survenant dans les régions fémorales des chiens.(Traduit par Dr Serge Messier).

Protocol of a pilot randomized clinical trial to evaluate nutritional support and rehabilitation on prevention of skeletal muscle mass loss during neoadjuvant chemotherapy in patients with esophageal cancer.

BACKGROUND: Subtotal esophagectomy with lymph node dissection followed by neoadjuvant chemotherapy (NAC) is the standard treatment for stage II-III esophageal cancer. Esophagectomy is still associated with high morbidity rates, and reducing these rates remains challenging. Among several complications, postoperative pneumonia (PP) is sometimes fatal, which has been reportedly caused by sarcopenia. Thus, nutritional support and rehabilitation may be promising for preventing skeletal muscle mass loss and reduce the incidence of PP. METHODS: This single-center, randomized, open-label, pilot trial will randomize a total of 40 patients with esophageal cancer in a 1:1 ratio either to ISOCAL Clear + rehabilitation arm or only rehabilitation arm. Although all patients will be educated about rehabilitation by a specialized physician and will be asked to undergo the prespecified rehabilitation program, patients treated with ISOCAL Clear + rehabilitation arm will be supplemented by 400 mL of ISOCAL Clear (Nestlé Japan Ltd, Tokyo, Japan) per day during two courses of NAC with docetaxel, cisplatin, and fluorouracil. Body composition will be assessed using Inbody (Inbody Co., Ltd., Tokyo, Japan) just before starting NAC and surgery. The primary endpoint is the change of skeletal muscle index (SMI) during NAC. Secondary endpoints include (i) body weight, total skeletal muscle mass, appendicular skeletal muscle mass, and lean body mass index changes; (ii) the percentage of ISOCAL Clear continuation; (iii) appetite evaluation; (iv) the percentage of targeted calorie achievement; (v) adverse events of NAC; (vi) postoperative complication rates; and (vii) postoperative hospital stay. DISCUSSION: This prospective trial assesses the efficacy of nutritional support in addition to rehabilitation during NAC for patients with esophageal cancer. The results will be utilized in assessing whether the effects of nutritional support by ISOCAL Clear are promising or not and in planning future larger clinical trials.

Influence of Androgen Deprivation Therapy on the Development of Sarcopenia in Patients with Prostate Cancer: A Systematic Review.

The changes in body composition during androgen deprivation therapy (ADT) in patients suffering from prostate cancer (PCa) are recognized by professionals more often as biomarker for effective treatment. The aim of this study was to investigate the impact of ADT on the sarcopenia development in PCa. The following databases were used: PubMed, Embase, Web of Science and Scopus databases. Out of 2183 studies, 7 were included in this review. The fixed-effect model was used in the meta-analysis. A significant increase in SATI (Subcutaneous Adipose Tissue Index) of 0.32 (95% CI: 0.13-0.51) p = 0.001, decrease in SMI (Skeletal Muscle Index) of -0.38 (95% CI: -0.57 to -0.19) p < 0.0001, and SMD (Skeletal Muscle Density) of -0.46 (95% CI: -0.69 to -0.24) p < 0.0001 were observed. No statistical association was visible between ADT and changes in BMI (Body Mass Index), 0.05 (95% CI: -0.18-0.28), p = 0.686, and VATI (Visceral Adipose Tissue Index): 0.17 (95% CI: -0.02 to 0.37), p = 0.074. In conclusion, the ADT significantly contributes to the body composition changes and sarcopenia development.

A novel body composition risk score (B-Score) and overall survival among patients with nonmetastatic breast cancer.

BACKGROUND & AIMS: Measurements (amount, distribution, and radiodensity) of muscle and adipose tissue were reported to be individually associated with overall survival in patients with breast cancer. However, they were not typically combined to develop an overall risk score, which can identify patients at high risk of death and prioritize patients in need of dietary and lifestyle interventions. Thus, we aimed to develop a novel composite body composition risk score (B-Score). METHODS: We included 3105 patients with stage II or III breast cancer at Kaiser Permanente Northern California and Dana Farber Cancer Institute. From CT scans at diagnosis, we assessed areas and radiodensity of muscle and adipose tissue at the third lumber vertebrae. We considered skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and SAT radiodensity as they were independent prognostic factors for overall survival. Each measurement was dichotomized using optimal stratification, with low SMI (<40.1 cm2/m2), high SATI (≥75.7 cm2/m2), and high SAT radiodensity (≥-97.2HU) considered risk factors. We calculated B-Score as the sum of these factors and estimated its association with overall survival using Cox proportional hazards regression with adjustment for clinicopathologic factors. RESULTS: Mean (standard deviation) age was 53.9 (11.8) years, 70.3% were Non-Hispanic White, and 60.5% were stage II. Most patients (60.6%) had only one body composition risk factor (B-Score = 1). Compared to those with no risk factors (B-Score = 0), the risk of death increased with more body composition risk factors: the adjusted hazard ratios were 1.10 (95% CI: 0.85, 1.42), 1.47 (95% CI: 1.12, 1.92), and 2.11 (95% CI: 1.26, 3.53) for B-Scores of 1, 2, and 3, respectively (Ptrend < 0.001). CONCLUSIONS: More unfavorable body composition characteristics were associated with increased risks of overall mortality in a dose-response manner. Considering body composition measurements together as a composite score (B-Score) may improve risk stratification and inform dietary and lifestyle interventions following breast cancer diagnosis.

Whey Peptide Alleviates Muscle Atrophy by Strongly Regulating Myocyte Differentiation in Mice.

Background and Objectives: Muscle atrophy occurs when protein degradation exceeds protein synthesis, resulting in imbalanced protein homeostasis, compromised muscle contraction, and a reduction in muscle mass. The incidence of muscle atrophy is increasingly recognized as a significant worldwide public health problem. The aim of the current study was to evaluate the effect of whey peptide (WP) on muscle atrophy induced by dexamethasone (DEX) in mice. Materials and Methods: C57BL/6 mice were divided into six groups, each consisting of nine individuals. WPs were orally administered to C57BL/6 mice for 6 weeks. DEX was administered for 5-6 weeks to induce muscle atrophy (intraperitoneal injection, i.p.). Results: Microcomputer tomography (CT) analysis confirmed that WP significantly increased calf muscle volume and surface area in mice with DEX-induced muscle atrophy, as evidenced by tissue staining. Furthermore, it increased the area of muscle fibers and facilitated greater collagen deposition. Moreover, WP significantly decreased the levels of serum biomarkers associated with muscle damage, kidney function, and inflammatory cytokines. WP increased p-mTOR and p-p70S6K levels through the IGF-1/PI3K/Akt pathway, while concurrently decreasing protein catabolism via the FOXO pathway. Furthermore, the expression of proteins associated with myocyte differentiation increased noticeably. Conclusions: These results confirm that WP reduces muscle atrophy by regulating muscle protein homeostasis. Additionally, it is believed that it helps to relieve muscle atrophy by regulating the expression of myocyte differentiation factors. Therefore, we propose that WP plays a significant role in preventing and treating muscle wasting by functioning as a supplement to counteract muscle atrophy.

Pathologic Features of Anti-Ku Myositis.

OBJECTIVE: Characteristics of myositis with anti-Ku antibodies are poorly understood. The purpose of this study was to elucidate the pathologic features of myositis associated with anti-Ku antibodies, compared with immune-mediated necrotizing myopathy (IMNM) with anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, in muscle biopsy-oriented registration cohorts in Japan and Germany. METHODS: We performed a retrospective pathology review of patients with anti-Ku myositis samples diagnosed in the Japanese and German cohorts. We evaluated histologic features and performed HLA phenotyping. RESULTS: Fifty biopsied muscle samples in the Japanese cohort and 10 in the German cohort were obtained. After exclusion of myositis-specific autoantibodies or other autoimmune connective tissue diseases, 26 samples (43%) of anti-Ku antibody-positive myositis were analyzed. All the samples shared some common features with IMNM, whereas they showed expression of MHC class II and clusters of perivascular inflammatory cells more frequently than the anti-SRP/HMGCR IMNM samples (71% vs 7%/16%; p < 0.005/<0.005; 64% vs 0%/0%; p < 0.005/<0.005). Anti-Ku myositis biopsies could be divided into 2 subgroups based on the extent of necrosis and regeneration. The group with more abundant necrosis and regeneration showed a higher frequency of MHC class II expression and perivascular inflammatory cell clusters. HLA phenotyping in the 44 available patients showed possible associations of HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA-DQB1*03:01 (p = 0.0045, 0.019, and 0.027; odds ratio [OR] 50.2, 4.6, and 2.8; 95% CI 2.6-2942.1, 1.1-14.5, and 1.0-7.0) in the group with less conspicuous necrosis and regeneration. On the contrary, in the group of more abundant necrosis and regeneration, the allele frequencies of HLA-A*24:02, HLA-B*52:01, HLA-C*12:02, and HLA-DRB1*15:02 were lower than those of healthy controls (p = 0.0036, 0.027, 0.016, and 0.026; OR = 0.27, 0, 0, and 0; 95% CI 0.1-0.7, 0-0.8, 0-0.8, and 0-0.8). However, these HLA associations did not remain significant after statistical correction for multiple testing. DISCUSSION: While anti-Ku myositis shows necrotizing myopathy features, they can be distinguished from anti-SRP/HMGCR IMNM by their MHC class II expression and clusters of perivascular inflammatory cells. The HLA analyses suggest that anti-Ku myositis may have different subsets associated with myopathologic subgroups.

The choice of diagnostic modality influences the proportion of low muscle strength, low muscle mass, and sarcopenia in colorectal cancer patients.

BACKGROUND AND AIMS: Low muscle strength, low muscle mass, and sarcopenia have a negative impact on health outcomes in colorectal cancer (CRC) patients. Different diagnostic modalities are used to identify these conditions but it is unknown how well the modalities agree. The aim of this study was to compare different diagnostic modalities by means of calculating the proportion of low muscle strength, low muscle mass, and sarcopenia in CRC patients, and to investigate the agreement for sarcopenia between the various modalities. METHODS: Men and women participating in the Norwegian Dietary Guidelines and colorectal cancer Survival (CRC-NORDIET) study were included in the analyses. Cut-off values for low muscle strength, low muscle mass, and sarcopenia were defined according to the second consensus set by the European Working Group on Sarcopenia in Older People (EWGSOP2). The diagnostic modalities used to assess muscle strength were handgrip strength and the sit-to-stand test. For muscle mass, computed tomography, dual-energy X-ray absorptiometry (DXA), multi-frequency bioelectrical impedance analysis (MF-BIA), and single-frequency BIA (SF-BIA) were applied. Cohen's kappa was calculated to determine the agreement for low muscle strength and confirmed sarcopenia between diagnostic modalities. RESULTS: Five hundred and three men and women (54 % men, mean age of 66 (range 50-80) years old) were included in the analysis. As much as 99 % (n = 70) of the population was identified with low muscle mass by MF-BIA, while the other modalities identified 9-49 % as having low muscle mass. Handgrip strength identified a lower proportion of low muscle strength as compared with the sit-to-stand test (4 % vs. 8 %). When applying various combinations of diagnostic modalities for low muscle strength and low muscle mass, the proportion of sarcopenia was found to be between 0.3 and 11.4 %. There was relatively poor agreement between the different diagnostic modalities with Cohen's Kappa ranging from 0.0 to 0.55, except for the agreement between SF-BIASergi and MF-BIASergi, which was 1. CONCLUSION: The proportion of low muscle strength, low muscle mass, and sarcopenia in CRC patients varied considerably depending on the diagnostic modalities used. Further studies are needed to provide modality-specific cut-off values, adjusted to sex, age and body size.

Association between adductor pollicis muscle thickness and low skeletal muscle mass index in community-dwelling older women undergoing outpatient rehabilitation.

OBJECTIVE: The performance of sarcopenia diagnosis using adductor pollicis muscle thickness (APMT) has been reported. However, the relationship between APMT and low skeletal muscle mass index (SMI) is unclear. The purpose of this study is to investigate the relationship between APMT and low SMI and APMT performance to diagnose low SMI in community-dwelling older women undergoing outpatient rehabilitation. METHODS: This study included 65 older women (mean age: 86.4 years). Subjects were received outpatient rehabilitation one to three times a week. The main outcomes were low SMI as diagnosed using the Asian working group for sarcopenia 2019 and APMT. Logistic regression analysis was performed with low SMI as the dependent variable, APMT, and propensity score calculated using age, sex, number of medications, and updated Charlson comorbidity index as the independent variable. A receiver operating characteristic (ROC) curve of APMT for low SMI was created. A cut-off value was calculated using the Youden index. RESULTS: Among the 65 subjects, 45 (69.2 %) had low SMI. The results of the logistic regression analysis showed a significant association between APMT and low SMI (odds ratio: 0.482 {95 % confidence interval [CI]: 0.313-0.744}). The cut-off value of APMT calculated from the ROC curve was 13 mm. The sensitivity and specificity of this cut-off value were 0.800 (95 % CI: 0.654-0.904) (36 out of 45 subjects) and 0.850 (95 % CI: 0.621-0.968) (17 out of 20 subjects), respectively. The positive predictive value, negative predictive value, and area under the curve were 0.923 (95 % CI: 0.791-0.984), 0.654 (95 % CI: 0.443-0.828), and 0.843 (95 % CI: 0.731-0.955), respectively. The APMT cut-off value of 13 mm is good to identify low SMI. CONCLUSIONS: The results of this study show that APMT is associated with low SMI. Furthermore, the cut-off value of APMT for diagnosing low SMI was 13 mm. The APMT cut-off value of 13 mm is good to identify low SMI. Our findings indicate that measuring APMT is useful for diagnosing low SMI in community-dwelling older women undergoing outpatient rehabilitation.

Muscle attenuation, not skeletal muscle index, is an independent prognostic factor for survival in gastric cancer patients with overweight and obesity.

OBJECTIVES: Skeletal muscle index (SMI) is insufficient for evaluating muscle in obesity, and muscle attenuation (MA) may be a preferred indicator. This study aimed to investigate whether MA has greater prognostic value than SMI in gastric cancer patients with overweight and obesity. METHODS: Clinical parameters of 1312 patients with gastric cancer who underwent radical gastrectomy were prospectively collected between 2013 and 2019. MA and SMI were analyzed by computed tomography scan. Overweight/obesity was defined as body mass index (BMI) ≥24 kg/m2. The hazard ratio (HR) for death was calculated using Cox regression analysis. RESULTS: Among all patients, 405 were identified as overweight and obese, and 907 were identified as normal and underweight. MA was inversely associated with BMI and visceral fat area. Among the 405 patients with overweight and obesity, 212 patients (52%) were diagnosed with low MA. In the overweight/obese group, MA was an independent predictor for overall survival (HR, 1.610; P = 0.021) in multivariate Cox regression analyses, whereas SMI did not remain in the model. In the normal/underweight group, both low MA (HR, 1.283; P = 0.039) and low SMI (HR, 1.369; P = 0.008) were independent factors of overall survival. Additionally, 318 patients were identified as having visceral obesity in the overweight/obese group, and low MA was also an independent prognostic factor for survival in these patients (HR, 1.765; P = 0.013). CONCLUSION: MA had a higher prognostic value than SMI in overweight and obese patients with gastric cancer after radical gastrectomy.

Restoration of epigenetic impairment in the skeletal muscle and chronic inflammation resolution as a therapeutic approach in sarcopenia.

Sarcopenia is an age-associated loss of skeletal muscle mass, strength, and function, accompanied by severe adverse health outcomes, such as falls and fractures, functional decline, high health costs, and mortality. Hence, its prevention and treatment have become increasingly urgent. However, despite the wide prevalence and extensive research on sarcopenia, no FDA-approved disease-modifying drugs exist. This is probably due to a poor understanding of the mechanisms underlying its pathophysiology. Recent evidence demonstrate that sarcopenia development is characterized by two key elements: (i) epigenetic dysregulation of multiple molecular pathways associated with sarcopenia pathogenesis, such as protein remodeling, insulin resistance, mitochondria impairments, and (ii) the creation of a systemic, chronic, low-grade inflammation (SCLGI). In this review, we focus on the epigenetic regulators that have been implicated in skeletal muscle deterioration, their individual roles, and possible crosstalk. We also discuss epidrugs, which are the pharmaceuticals with the potential to restore the epigenetic mechanisms deregulated in sarcopenia. In addition, we discuss the mechanisms underlying failed SCLGI resolution in sarcopenia and the potential application of pro-resolving molecules, comprising specialized pro-resolving mediators (SPMs) and their stable mimetics and receptor agonists. These compounds, as well as epidrugs, reveal beneficial effects in preclinical studies related to sarcopenia. Based on these encouraging observations, we propose the combination of epidrugs with SCLI-resolving agents as a new therapeutic approach for sarcopenia that can effectively attenuate of its manifestations.

Quantifying the severity of sarcopenia in patients with cancer of the head and neck.

BACKGROUND & AIMS: Existing skeletal muscle index (SMI) thresholds for sarcopenia are inconsistent, and do not reflect severity of depletion. In this study we aimed to define criterion values for moderate and severe skeletal muscle depletion based on the risk of mortality in a population of patients with head and neck cancer (HNC). Additionally, we aimed to identify clinical and demographic predictors of skeletal muscle depletion, evaluate the survival impact of skeletal muscle depletion in patients with minimal nutritional risk or good performance status, and finally, benchmarking SMI values of patients with HNC against healthy young adults. METHODS: Population cohort of 1231 consecutive patients and external validation cohorts with HNC had lumbar SMI measured by cross-sectional imaging. Optimal stratification determined sex-specific thresholds for 2-levels of SMI depletion (Class I and II) based on overall survival (OS). Adjusted multivariable regression analyses (tumor site, stage, performance status, age, sex, dietary intake, weight loss) determined relationships between 2-levels of SMI depletion and OS. RESULTS: Mean SMI (cm2/m2) was 51.7 ± 9.9 (males) and 39.8 ± 7.1 (females). The overall and sex-specific population demonstrated an increased risk of mortality associated with decreasing SMI. Sex-specific SMI (cm2/m2) depletion thresholds for 2-levels of muscle depletion determined by optimal stratification for males and females, respectively (male: 45.2-37.5, and <37.5; female: 40.9-34.2, and <34.2). In the overall population, Normal SMI, Class I and II SMI depletion occurred in 65.0%, 24.0%, and 11.0%, respectively. Median OS was: Normal SMI (114 months, 95% CI, 97.1-130.8); Class I SMI Depletion (42 months, 95% CI, 28.5-55.4), and Class II SMI Depletion (15 months, 95% CI, 9.8-20.1). Adjusted multivariable analysis compared with Normal SMI (reference), Class I SMI Depletion (HR, 1.49; 95% CI, 1.18-1.88; P < .001), Class II SMI Depletion (HR, 1.91; 95% CI, 1.42-2.58; P < .001). CONCLUSIONS: Moderate and severe SMI depletion demonstrate discrimination in OS in patients with HNC. Moderate and severe SMI depletion is prevalent in patients with minimal nutrition risk and good performance status. Benchmarking SMI values against healthy young adults exemplifies the magnitude of SMI depletion in patients with HNC and may be a useful method in standardizing SMI assessment.

Paraneoplastic myopathies.

This chapter reviews the association between cancer and the idiopathic inflammatory myopathies (IIM), which includes dermatomyositis (DM), antisynthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Accumulating evidence shows that the risk of a coexisting malignancy is high in patients with DM, especially among those with anti-Tif1γ autoantibodies. Patients with IMNM and no defined autoantibodies also have an increased risk of malignancy. Recent evidence demonstrates that many IBM patients have increased numbers of circulating CD57+ CD8+ T cells, consistent with a diagnosis of large granular lymphocytic leukemia. In contrast, IMNM patients with anti-SRP or anti-HMGCR autoantibodies as well as patients with ASyS syndrome do not have a definitively increased risk of cancer. Patients who have a cancer treated with one of the immune checkpoint inhibitors can develop myositis (ICI-myositis), sometimes along with myasthenia gravis and/or myocarditis.

HIV-associated nemaline myopathy manifesting as bent spine syndrome.

HIV-associated myopathies include HIV-associated polymyositis, inclusion body myositis, diffuse infiltrative lymphocytosis syndrome and sporadic late-onset nemaline myopathy (HIV-NM). HIV-NM typically manifests as a painless, progressive proximal and axial muscle weakness with characteristic histological findings of intracytoplasmic rods, or nemaline bodies, seen in atrophic muscle fibres. HIV-NM presents prior to or shortly after initiation of antiretroviral therapy (ART) and is treated with intravenous immunoglobulin, glucocorticoids or immunosuppression. We present a case of HIV-NM in a patient with well-controlled HIV on decades-long ART with progressive bent spine syndrome, or camptocormia. This case highlights the importance of considering HIV-associated myopathies such as HIV-NM in patients with HIV who present with musculoskeletal complaints.

Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti-inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight-week-old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF-κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF-κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD.

Low vitamin D levels accelerates muscle mass loss in patients with chronic liver disease.

Sarcopenia frequently and progressively occurs in patients with chronic liver disease. This study aimed to clarify the relationship between vitamin D levels and muscle mass loss. A total of 166 patients with chronic liver disease were enrolled in this study. Skeletal muscle mass index (SMI) was measured by bioelectrical impedance analysis at baseline and after 1 year. The rate of change in SMI from baseline after 1 year was calculated: ΔSMI (%) = [(1-year SMI - baseline SMI) / baseline SMI] × 100. Muscle mass loss was defined as ΔSMI ≤ -2%. The median 25-hydroxyvitamin D was 15.2 (11.2-19.3) ng/mL. The median SMI were 6.8 (5.9-7.8) kg/m2 at baseline and 6.7 (5.9-7.6) kg/m2 after 1 year. The median ΔSMI was -1.23% (-2.21% to 1.61%). Multivariate analysis identified low 25-hydroxyvitamin D as an independent factor associated with muscle mass loss. The optimal cut-off value of 25-hydroxyvitamin D to predict muscle mass loss was 12.7 ng/mL. Muscle mass loss was found in 56.4% v.s. 18.0% of patients with 25-hydroxyvitamin D < 12.7 vs. ≥ 12.7 ng/mL, respectively (p = 9.01 × 10-7); with the highest incidence in patients with non-alcoholic fatty liver disease (NAFLD). Specifically, patients with NAFLD and 25-hydroxyvitamin D < 12.7 ng/mL had a significantly higher incidence of muscle mass loss than those with ≥ 12.7 ng/mL (p = 1.23 × 10-3). Low vitamin D levels are associated with muscle mass loss after 1 year in patients with chronic liver disease, especially NAFLD.

Sarcopenic obesity and the impact on bone health.

PURPOSE OF REVIEW: Sarcopenic obesity is a newly identified pathological entity defined by an increase in body fat mass with an associated sarcopenia, characterized by loss of muscle mass, strength, and function. Recently, the concomitant presence of skeletal alteration with sarcopenic obesity has been described leading to a new clinical entity defined osteosarcopenic obesity (OSO). Many studies have tried to unravel the metabolic complex mechanism leading to this clinical entity in order to understand the pathophysiology of this complex condition with the aim of posing an early diagnosis to improve the therapeutic approaches. The purpose of this narrative review is to highlight and revise recent studies on this issue. RECENT FINDINGS: Recent research in the field of OSO has highlighted the role of nutrition and physical activity in the development and management of these conditions. While molecular and cellular pathways remain partially understood, there is a growing focus on lifestyle interventions as key factors in reducing the impact of OSO. These studies emphasize the need for early diagnosis and appropriate therapeutic strategies to improve quality of life and decrease morbidity and mortality associated with OSO. SUMMARY: Although the pathophysiological pathways underlying OSO are not fully understood, the clinical implications underscore the need for expanded research in this field. This research is crucial for enabling early diagnosis and implementing effective therapeutic interventions, with the goal of reducing morbidity and mortality and enhancing quality of life.