The Atrophic Effect of 1,25(OH)2 Vitamin D3 (Calcitriol) on C2C12 Myotubes Depends on Oxidative Stress

Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle loss, the efficacy of VD supplementation to overcome muscle wasting is debated. Investigations on the direct effects of VD metabolites on skeletal muscle using C2C12 myotubes have revealed an unexpected pro-atrophic activity of calcitriol (1,25VD), while its upstream metabolites cholecalciferol (VD3) and calcidiol (25VD) have anti-atrophic effects. Here, we investigated if the atrophic effects of 1,25VD on myotubes depend on its activity on mitochondrial metabolism. The impact of 1,25VD and its upstream metabolites VD3 and 25VD on mitochondria dynamics and the activity of C2C12 myotubes was evaluated by measuring mitochondrial content, architecture, metabolism, and reactive oxygen species (ROS) production. We found that 1,25VD induces atrophy through protein kinase C (PKC)-mediated ROS production, mainly of extramitochondrial origin. Consistent with this, cotreatment with the antioxidant N-acetylcysteine (NAC), but not with the mitochondria-specific antioxidant mitoTEMPO, was sufficient to blunt the atrophic activity of 1,25VD. In contrast, VD3 and 25VD have antioxidant properties, suggesting that the efficacy of VD supplementation might result from the balance between atrophic pro-oxidant (1,25VD) and protective antioxidant (VD3 and 25VD) metabolites.

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The Impact of Critical Illness on Skeletal Muscle Structure

10.1093/med/9780199653461.003.0034 ◽

2014 ◽

Author(s):

Catherine L Hough

Keyword(s):

Skeletal Muscle ◽

Critical Illness ◽

Thick Filament ◽

Muscle Membrane ◽

Type I ◽

Muscle Loss ◽

Muscle Structure ◽

Muscle Necrosis ◽

Skeletal Muscle Loss ◽

The Impact

Patients with critical illness are at risk of profound weakness and skeletal muscle loss, and recovery is marked by prolonged physical functional impairment in many survivors. Muscle and nerve abnormalities found in critically ill patients include loss of muscle mass, muscle membrane inexcitability, polyneuropathy, mitochondrial dysfunction with bioenergetic failure, as well as changes in skeletal muscle structure. The most common histological abnormalities are atrophy of both type I and II fibres and thick filament loss; muscle necrosis is less common. While recent studies have illuminated the pathogenesis of critical illness myopathy, additional high-quality translational research is needed to identify targets for therapeutic intervention.

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The impact of skeletal muscle loss for hepatocellular carcinoma treated with lenvatinib.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.493 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 493-493

Author(s):

Mao Okada ◽

Hiroyuki Nakanishi ◽

Masayuki Kurosaki ◽

Kento Inada ◽

Sakura Kirino ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Skeletal Muscle ◽

Dose Intensity ◽

Muscle Loss ◽

Muscle Area ◽

Chronological Change ◽

Significant Difference ◽

Skeletal Muscle Loss ◽

Tki Treatment ◽

The Impact

493 Background: Many previous reports have shown that skeletal muscle loss (SML) is one of the prognostic factors for hepatocellular carcinoma (HCC) patients treated with sorafenib. However, there are few reports about the impact of SML for the HCC patients treated with lenvatinib. Therefore, we evaluated the relation between SML and overall survival (OS) of HCC patients treated with lenvatinib (LEN). Methods: We retrospectively analyzed 50 HCC patients treated with LEN from April 2018 to February 2019. We included 36 patients who continued LEN more than 8 weeks and evaluated CT scans before treatment and after 8 weeks. Skeletal muscle area was measured on axial image at the level of the third lumber vertebra (L3) using sliceOmatic. Skeletal Mass Index (SMI) was calculated by dividing the muscle area (㎠) with square of height (㎡). The definition of myopenia is based on the guideline described by the Japan Society of Hepatology (42㎠/㎡ in men and 38 ㎠/㎡ in women). ΔSMI is a chronological change of SMI for 8 weeks. We calculated decreasing rate of ΔSMI. We evaluated the relation between chronological change of SMI and OS. Results: The patients with myopenia at baseline were 12 (33.3 %). The decreasing rate of ΔSMI at 8 weeks was -2.57 % [-5.9, 0.2]. SMI had decreased in 27 patients (75 %) for 8 weeks. There was no significant difference between OS and baseline myopenia (p = 0.2), ALBI grade (p = 0.2), BCLC stage (p = 0.5), up to 7 in or out (p = 0.35), previous TKI treatment (p = 0.15), metastasis (p = 0.91), or vascular invasion (p = 0.12). However, the patients who had decreased SMI had significantly poor prognosis (p = 0.028). In backgrounds, there was no significant difference between patients with or without decreasing of ΔSMI, such as baseline myopenia (p = 0.7), ALBI grade (p = 0.4), BCLC stage (p = 1.0), Child Pugh score (p = 0.8), age (p = 0.6), sex (p = 0.3), up to7 in or out (p = 1.0), previous TKI treatment (p = 0.3), and relative dose intensity at 4 weeks (p = 0.9). Conclusions: There was no significant correlation between baseline myopenia and OS. However, chronological decreasing of SMI for 8 weeks was a prognostic factor of HCC patients treated with LEN. Therefore, monitoring and preventing of decreasing of skeletal muscle mass may be important.

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Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges

Nutrients ◽

10.3390/nu12103101 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3101

Author(s):

Emanuele Rinninella ◽

Marco Cintoni ◽

Pauline Raoul ◽

Carmelo Pozzo ◽

Antonia Strippoli ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Nutritional Support ◽

Muscle Wasting ◽

Early Recognition ◽

Clinical Implications ◽

Molecular Pathways ◽

Muscle Loss ◽

Skeletal Muscle Loss ◽

The Impact

In cancer patients, loss of muscle mass is significantly associated with low tolerability of chemotherapy and poor survival. Despite the great strides in the treatment of cancer, targeted therapies such as tyrosine kinase inhibitors (TKIs) could exacerbate muscle wasting. Over recent years, the impact of skeletal muscle loss during TKI therapy on clinical outcomes has been in the spotlight. In this review, we focus on the different molecular pathways of TKIs potentially involved in muscle wasting. Then, we report the results of the studies assessing the effects of different TKI therapies—such as sorafenib, regorafenib, sunitinib, and lenvatinib—on muscle mass, and highlight their potential clinical implications. Finally, we discuss an integrative nutritional approach to be adopted during TKI treatment. The assessment of muscle mass from computerized tomography imaging could be helpful in predicting toxicity and prognosis in patients treated with TKI such as sorafenib. Early recognition of low muscle mass and effective personalized nutritional support could prevent or attenuate muscle mass wasting. However, the role of nutrition is still overlooked, and future clinical trials are needed to find the optimal nutritional support to countermeasure muscle mass depletion during TKI therapy.

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Association between Skeletal Muscle Loss and the Response to Neoadjuvant Chemotherapy for Breast Cancer

Cancers ◽

10.3390/cancers13081806 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1806

Author(s):

Byung Min Lee ◽

Yeona Cho ◽

Jun Won Kim ◽

Sung Gwe Ahn ◽

Jee Hung Kim ◽

...

Keyword(s):

Breast Cancer ◽

Skeletal Muscle ◽

Neoadjuvant Chemotherapy ◽

Cancer Patients ◽

Muscle Loss ◽

Breast Cancer Patients ◽

Skeletal Muscle Index ◽

Skeletal Muscle Loss ◽

The Impact ◽

Response To Neoadjuvant Chemotherapy

There are no means to predict patient response to neoadjuvant chemotherapy (NAC); the impact of skeletal muscle loss on the response to NAC remains undefined. We investigated the association between response to chemotherapy and skeletal muscle loss in breast cancer patients. Patients diagnosed with invasive breast cancer who were treated with NAC, surgery, and radiotherapy were analyzed. We quantified skeletal muscle loss using pre-NAC and post-NAC computed tomography scans. The response to treatment was determined using the Response Evaluation Criteria in Solid Tumors. We included 246 patients in this study (median follow-up, 28.85 months). The median age was 48 years old (interquartile range 42–54) and 115 patients were less than 48 years old (46.7%). Patients showing a complete or partial response were categorized into the responder group (208 patients); the rest were categorized into the non-responder group (38 patients). The skeletal muscle mass cut-off value was determined using a receiver operating characteristic curve; it showed areas under the curve of 0.732 and 0.885 for the pre-NAC and post-NAC skeletal muscle index (p < 0.001 for both), respectively. Skeletal muscle loss and cancer stage were significantly associated with poor response to NAC in locally advanced breast cancer patients. Accurately measuring muscle loss to guide treatment and delaying muscle loss through various interventions would help enhance the response to NAC and improve clinical outcomes.

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ASO Author Reflections: The Impact of Early Skeletal Muscle Loss Within 1 Week After Esophagectomy on Long-term Prognosis in Patients with Esophageal Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-021-09670-z ◽

2021 ◽

Author(s):

Kazuaki Matsui ◽

Hirofumi Kawakubo ◽

Yuki Hirata ◽

Satoru Matsuda ◽

Shuhei Mayanagi ◽

...

Keyword(s):

Skeletal Muscle ◽

Esophageal Cancer ◽

Muscle Loss ◽

Skeletal Muscle Loss ◽

Long Term Prognosis ◽

The Impact

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Impact of Endovascular Treatment on Leg Muscle Mass in Peripheral Artery Disease: a Preliminary Report

10.21203/rs.3.rs-21826/v1 ◽

2020 ◽

Author(s):

Tomoyo Miyakuni ◽

Hidenori Komiyama ◽

Masamichi Takano ◽

Takeshi Ikeda ◽

Masato Matsushita ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Lower Limbs ◽

Thigh Muscle ◽

Muscle Loss ◽

Peripheral Artery ◽

Muscle Area ◽

Skeletal Muscle Loss ◽

Artery Disease ◽

The Impact

Abstract Background: Peripheral artery disease (PAD), intermittent claudication, and impaired mobility lower patients’ quality of life, contributing to the loss of skeletal muscle. This study sought to investigate the impact of endovascular treatment (EVT) by measuring the mid-thigh level of muscle volume in above the knee PAD patients before and after EVT.Methods: In this prospective, observational study, symptomatic PAD patients with above the knee lesions who had intermittent claudication and were undergoing optimal medical treatment were enrolled. The mid-thigh level of muscle area was measured by computed tomography initially, and then 3 and 6 months after EVT. Patients were categorized into ipsilateral or bilateral based on clinical symptoms and initial ABI value. The muscle area in ischemic and non-ischemic legs were compared in ipsilateral PAD patients. The correlations between alterations in the total thigh muscle area and clinical characteristics were analyzed in univariable and multivariable analysis to investigate the factor contributing skeletal muscle loss.Results: A total of 22 patients were analyzed. The muscle area of the thighs increased after EVT. Fourteen patients had ipsilateral lesions and 8 had bilateral stenosis. In patients with ipsilateral lesions, the mid-thigh muscle area of ischemic lower limbs was significantly lesser than that of non-ischemic lower limbs (118.2±16.5 cm2 vs 124.0±17.3 cm2, p=0.0002). The thigh muscle area of ischemic lower limbs increased after EVT (before: 118.2±16.5 cm2 vs 3 months: 124.0±18.7 cm2, p=0.0166; before vs 6 months: 123.0±17.7 cm2, p= 0.0566), but this was not the case for non-ischemic lower limbs. Multivariate regression analysis revealed that baseline glycated hemoglobin was the only factor that negatively correlated with the change in the muscle area after 3 (β= -3.74, 95% confidence interval [CI] = -7.3 to -0.2, p=0.0417) and 6 months (β= -5.24, 95%CI = -10.1 to -0.4, p=0.03567). Muscle area significantly increased in normoglycemic HbA1c < 6.5 patients (before: 246.1±33.5 cm2, before vs 3 months: 249.6±34.6 cm2, p = 0.032, before vs 6 months: 250.6±35.7 cm2, p = 0.0455) while there was no significant alternation in hyperglycemic (HbA1c ≥ 6.5) patients (before: 225.2±43.4 cm2, 3 months: 224.6±44.8 cm2, 6 months: 222.2±45.5 cm2).Conclusions: Ischemia induces muscle atrophy in PAD patients. However, ischemic muscle atrophy was ameliorated after EVT in normoglycemic patients. There is a need for large scale trial to investigate the impact of EVT if it would protect or even delay skeletal muscle loss in all-comer population.

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