bims-aucach 2022-02-06 papers

Issue of 2022‒02‒06
six papers selected by
Kleiton Silva
Rowan University

J Cachexia Sarcopenia Muscle. 2022 Jan 30.

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

Xiangkun Meng, Zhe Huang, Aiko Inoue, Hailong Wang, Ying Wan, Xueling Yue, Shengnan Xu, Xueying Jin, Guo-Ping Shi, Masafumi Kuzuya, Xian Wu Cheng.

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.

Keywords: Cachexia; Cathepsin K; Insulin receptor substrate 1; Muscle wasting; Ubiquitination

DOI: https://doi.org/10.1002/jcsm.12919

Transl Cancer Res. 2021 Jun;10(6): 3020-3032

Regulation of dynamin-related protein 1 (DRP1) levels modulates myoblast atrophy induced by C26 colon cancer-conditioned medium.

Xiangyu Mao, Qingyang Meng, Jun Han, Lei Shen, Xiangyu Sui, Yihua Gu, Guohao Wu.

Background: Cancer associated-cachexia, which involves progressive skeletal muscle loss, is induced by multiple factors. However, the underlying mechanism remains unclear. Dynamin-related protein 1 (DRP1), a major modulator of mitochondrial fission, has been reported to participate in muscle turnover. This study aimed to explore the role of DRP1 in muscle during the process of cancer associated-cachexia (CAC) via an in vitro model and the mechanisms involved.Methods: C26 colon cancer cell-conditioned medium (CM) was used to incubate with C2C12 myotubes to simulate cachexia. Myotubes were then transduced with lentiviral vectors of DRP1-small interfering RNA (siRNA), DRP1 overexpression plasmid, or a control plasmid to regulate the DRP1 levels, and their diameters were assessed using a biological microscope. Furthermore, transcriptome sequencing was performed to screen the pathways involved, and real-time polymerase chain reaction (RT-PCR) was used for verification.
Results: The cachexia model was successfully established with a decreased myotube diameter and increased DRP1 expression. DRP1 knockdown significantly ameliorated myotube wasting during cachexia, while DRP1 overexpression intensified this phenomenon. Transcriptome sequencing indicated that DRP1 knockdown was associated with the activation of ribosomal biogenesis. However, PCR results showed that compared to the control, one of the ribosomal biogenesis marker's (Ubf) level was decreased by C26 CM, and DRP1 knockdown did not significantly restore its level.
Conclusions: During C26 CM-induced cachexia, DRP1 was activated, while the regulation of DRP1 levels was able to modulate the atrophy of C2C12 myotubes. The underlying mechanism of the alleviated muscle atrophy induced by DRP1 knockdown was likely associated with increased ribosomal activity.

Keywords: Cachexia; dynamins; muscular atrophy; neoplasms; ribosomes

DOI: https://doi.org/10.21037/tcr-21-751

Sports Med. 2022 Feb 04.

Exercise-Based Interventions to Counteract Skeletal Muscle Mass Loss in People with Cancer: Can We Overcome the Odds?

Kelcey A Bland, Imre W K Kouw, Luc J C van Loon, Eva M Zopf, Ciaran M Fairman.

Addressing skeletal muscle mass loss is an important focus in oncology research to improve clinical outcomes, including cancer treatment tolerability and survival. Exercise is likely a necessary component of muscle-mass-preserving interventions for people with cancer. However, randomized controlled trials with exercise that include people with cancer with increased susceptibility to more rapid and severe muscle mass loss are limited. The aim of the current review is to highlight features of cancer-related skeletal muscle mass loss, discuss the impact in patients most at risk, and describe the possible role of exercise as a management strategy. We present current gaps within the exercise oncology literature and offer several recommendations for future studies to support research translation, including (1) utilizing accurate and reliable body composition techniques to assess changes in skeletal muscle mass, (2) incorporating comprehensive assessments of patient health status to allow personalized exercise prescription, (3) coupling exercise with robust nutritional recommendations to maximize the impact on skeletal muscle outcomes, and (4) considering key exercise intervention features that may improve exercise efficacy and adherence. Ultimately, the driving forces behind skeletal muscle mass loss are complex and may impede exercise tolerability and efficacy. Our recommendations are intended to foster the design of high-quality patient-centred research studies to determine whether exercise can counteract muscle mass loss in people with cancer and, as such, improve knowledge on this topic.

DOI: https://doi.org/10.1007/s40279-021-01638-z

Kidney Res Clin Pract. 2022 Jan;41(1): 14-21

Skeletal muscle energetics in patients with moderate to advanced kidney disease.

Lale Ertuglu, Abdulmecit Yildiz, Jorge Gamboa, T Alp Ikizler.

Sarcopenia, defined as decrease in muscle function and mass, is common in patients with moderate to advanced chronic kidney disease (CKD) and is associated with poor clinical outcomes. Muscle mitochondrial dysfunction is proposed as one of the mechanisms underlying sarcopenia. Patients with moderate to advanced CKD have decreased muscle mitochondrial content and oxidative capacity along with suppressed activity of various mitochondrial enzymes such as mitochondrial electron transport chain complexes and pyruvate dehydrogenase, leading to impaired energy production. Other mitochondrial abnormalities found in this population include defective beta-oxidation of fatty acids and mitochondrial DNA mutations. These changes are noticeable from the early stages of CKD and correlate with severity of the disease. Damage induced by uremic toxins, oxidative stress, and systemic inflammation has been implicated in the development of mitochondrial dysfunction in CKD patients. Given that mitochondrial function is an important determinant of physical activity and performance, its modulation is a potential therapeutic target for sarcopenia in patients with kidney disease. Coenzyme Q, nicotinamide, and cardiolipin-targeted peptides have been tested as therapeutic interventions in early studies. Aerobic exercise, a well-established strategy to improve muscle function and mass in healthy adults, is not as effective in patients with advanced kidney disease. This might be due to reduced expression or impaired activation of peroxisome proliferator-activated receptor-gamma coactivator 1α, the master regulator of mitochondrial biogenesis. Further studies are needed to broaden our understanding of the pathogenesis of mitochondrial dysfunction and to develop mitochondrial-targeted therapies for prevention and treatment of sarcopenia in patients with CKD.

Keywords: Chronic renal insufficiency; Mitochondria; Muscles; Sarcopenia

DOI: https://doi.org/10.23876/j.krcp.21.175

Semin Dial. 2022 Feb 03.

Combining exercise and nutrition in chronic kidney disease and dialysis: Can we learn from the performance nutrition of athletes?

Anthony Meade, Carla McLaren, Paul N Bennett.

The benefits of exercise interventions in individuals with chronic kidney disease have been widely reviewed; however, exercise has not yet been incorporated into routine clinical practice. In athletic populations, the goals of exercise training are to improve a specific aspect of physical performance such as strength or endurance, to ultimately optimize physical performance. This contrasts with many chronic kidney disease exercise studies where the goals are more aligned to a minimal effect, such as prevention of decline in physical function, frailty or protein energy wasting (PEW), weight loss for cardiovascular disease risk reduction, and risk minimization for mortality. In athletic populations, there are common targeted nutrition strategies used to optimize physical performance. In this review, we consider the evidence for and potential benefits of targeted nutrition strategies to complement well-designed exercise interventions to improve physical performance in people with chronic kidney disease and dialysis. Overall, we found a small number of studies using targeted protein supplementation in combination with a variety of exercise protocols; however, results were mixed. Future studies in people with chronic kidney disease should optimize acute (pre, during, and postexercise) and chronic nutritional status, utilizing targeted nutrition interventions proven in athletes to have benefit.

DOI: https://doi.org/10.1111/sdi.13060

J Cachexia Sarcopenia Muscle. 2022 Feb 03.

Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload.

David Martin, Kévin Nay, François Robin, Amélie Rebillard, Luz Orfila, Brice Martin, Patricia Leroyer, Pascal Guggenbuhl, Suzanne Dufresne, Philippe Noirez, Martine Ropert, Olivier Loréal, Frédéric Derbré.

BACKGROUND: Iron excess has been proposed as an essential factor in skeletal muscle wasting. Studies have reported correlations between muscle iron accumulation and atrophy, either through ageing or by using experimental models of secondary iron overload. However, iron treatments performed in most of these studies induced an extra-pathophysiological iron overload, more representative of intoxication or poisoning. The main objective of this study was to determine the impact of iron excess closer to pathophysiological conditions on structural and metabolic adaptations (i) in differentiated myotubes and (ii) in skeletal muscle exhibiting oxidative (i.e. the soleus) or glycolytic (i.e. the gastrocnemius) metabolic phenotypes.METHODS: The impact of iron excess was assessed in both in vitro and in vivo models. Murine differentiated myotubes were exposed to ferric ammonium citrate (FAC) (i.e. 10 and 50 μM) for the in vitro component. The in vivo model was achieved by a single iron dextran subcutaneous injection (1 g/kg) in mice. Four months after the injection, soleus and gastrocnemius muscles were harvested for analysis.
RESULTS: In vitro, iron exposure caused dose-dependent increases of iron storage protein ferritin (P < 0.01) and dose-dependent decreases of mRNA TfR1 levels (P < 0.001), which support cellular adaptations to iron excess. Extra-physiological iron treatment (50 μM FAC) promoted myotube atrophy (P = 0.018), whereas myotube size remained unchanged under pathophysiological treatment (10 μM FAC). FAC treatments, whatever the doses tested, did not affect the expression of proteolytic markers (i.e. NF-κB, MurF1, and ubiquitinated proteins). In vivo, basal iron content and mRNA TfR1 levels were significantly higher in the soleus compared with the gastrocnemius (+130% and +127%; P < 0.001, respectively), supporting higher iron needs in oxidative skeletal muscle. Iron supplementation induced muscle iron accumulation in the soleus and gastrocnemius muscles (+79%, P < 0.001 and +34%, P = 0.002, respectively), but ferritin protein expression only increased in the gastrocnemius (+36%, P = 0.06). Despite iron accumulation, muscle weight, fibre diameter, and myosin heavy chain distribution remained unchanged in either skeletal muscle.
CONCLUSIONS: Together, these data support that under pathophysiological conditions, skeletal muscle can protect itself from the related deleterious effects of excess iron.

Keywords: Disuse; Mitochondria; Myosin heavy chain; Sarcopenia; Typology

DOI: https://doi.org/10.1002/jcsm.12897