Abstract BackgroundCancer cachexia (CC) impacts quality of life, physical function, anticancer treatment response, and survival. Inflammation is a prominent pathomechanism of CC. This small‐scale study sets out to investigate the immunomodulatory drug lenalidomide in inflammatory CC in a randomized, double‐blind, placebo‐controlled trial.MethodsPatients with advanced solid malignancies, documented weight loss, no or unchanged anticancer treatment, and C‐reactive protein > 30 mg/L were included. In a 2:2:1 randomization, patients received either lenalidomide 25 mg once daily or C‐reactive protein‐guided dose, starting with 5 mg lenalidomide once daily or placebo once a day for 8 weeks. Dose adaption and safety were assessed twice a week. Treatment response was defined as an increase of lean body mass of more than 2% in a lower lumbar computed tomography and an increase in dynamometer‐assessed handgrip strength of 4 kg. Secondary endpoints included adverse events, C‐reactive protein response, nutritional intake, and symptoms.ResultsOf 24 eligible patients, 16 were included (25% female). At baseline, the mean age was 67 (range 51–88) years, and mean body weight was 64.7 kg (range 39.8–87.2 kg). Five were diagnosed with mesothelioma, two with non‐small‐cell lung cancer, two with renal cell carcinoma, two with neuroendocrine tumours, and five with other malignancies. Mean survival was 43 days. Eleven adverse events (four of which were severe) were recorded with a probable link to study participation. Nine patients completed the study. No participant showed a treatment response. C‐reactive protein‐guided dosing did not result in lower doses of lenalidomide. Lean body mass decreased less in the treatment groups. For the lenalidomide and placebo groups respectively, handgrip strength decreased by 2.3 vs. 5.5 kg, nutritional intake decreased by 249 vs. 32 kcal/day, and C‐reactive protein increased by 35 mg/dL vs. decreased by 17 mg/dL. The study was closed prematurely due to slow accrual and the need for concurrent anticancer treatments.ConclusionsNo treatment response on muscle mass and muscle strength was observed with lenalidomide. Because of several limiting factors, including low recruitment caused in part by an ambitious study design and concomitant anticancer treatment, this study did not generate adequate data to draw reliable conclusions.

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Abstract BackgroundPre‐frailty has been identified as a clinically silent mechanism pre‐disposing people to frailty. The goal of this study is to investigate the impact of low‐dose metformin on pre‐diabetic pre‐frail patients (>50 years) on skeletal muscle mass, speed of gait, handgrip power, and health‐related quality of life (HR‐QoL).MethodsWe did a retrospective cohort study of subjects aged 50 years and older who were diagnosed with pre‐frailty (one or two criteria present based on Fried Frailty Index) and pre‐diabetes (HbA1c 5.7% to 6.4%) from May 2018 to April 2020. Subjects taking low‐dose metformin were compared with non‐metformin participants through a review of the medical records. The results were analysed at baseline and 6–12 months post‐prescription with or without metformin. All data were accompanied by a 95% confidence interval.ResultsOne hundred and thirteen pre‐diabetic and pre‐frail subjects were recruited to metformin [the mean metformin administration was 750 (140) mg/day] (n = 58) or control group (n = 55). The average age was 66.3 (6.8) years old, with 52.2% of the population being female. The baseline demographic, nutritional, physical, and mental status data did not differ between groups. In comparison with the control group, an 8.9 (1.8) month low‐dose metformin intervention resulted in a higher skeletal muscle mass index of 1.26 (1.66) kg/m2 (P = 0.029), a faster gait speed of 0.15 (0.22) m/s (P = 0.011), and a greater handgrip strength of 2.1 (2.9) kg (P = 0.037). However, there was no difference in myostatin serum levels or HR‐QoL between groups.ConclusionsLow‐dose metformin was statistically and clinically meaningful to improve the original skeletal muscle mass index, gait speed, and grip strength as part of the sarcopenia dimension, but the Euro Quality of Life‐5 Dimensions index and myostatin serum levels did not change significantly.

BackgroundLow muscle in cancer is associated with an increase in treatment-related toxicities and is a predictor of cancer-related and all-cause mortality. The mechanisms of cancer-related muscle loss are multifactorial, including anorexia, hypogonadism, anaemia, inflammation, malnutrition, and aberrations in skeletal muscle protein turnover and metabolism.MethodsIn this narrative review, we summarise relevant literature to (i) review the factors influencing skeletal muscle mass regulation, (ii) provide an overview of how cancer/treatments negatively impact these, (iii) review factors beyond muscle signalling that can impact the ability to participate in and respond to an exercise intervention to counteract muscle loss in cancer, and (iv) provide perspectives on critical areas of future research.ResultsDespite the well-known benefits of exercise, there remains a paucity of clinical evidence supporting the impact of exercise in cancer-related muscle loss. There are numerous challenges to reversing muscle loss with exercise in clinical cancer settings, ranging from the impact of cancer/treatments on the molecular regulation of muscle mass, to clinical challenges in responsiveness to an exercise intervention. For example, tumour-related/treatment-related factors (e.g. nausea, pain, anaemia, and neutropenia), presence of comorbidities (e.g. diabetes, arthritis, and chronic obstructive pulmonary disease), injuries, disease progression and bone metastases, concomitant medications (e.g., metformin), can negatively affect an individual’s ability to exercise safely and limit subsequent adaptation.ConclusionsThis review identifies numerous gaps and oppportunities in the area of low muscle and muscle loss in cancer. Collaborative efforts between preclinical and clinical researchers are imperative to both understanding the mechanisms of atrophy, and develop appropriate therapeutic interventions.

Abstract BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation, abnormal body composition, and an increased risk for sarcopenia. Muscle wasting in turn increases the risk of infection, morbidity, and premature mortality, but little is known of the relation between nutrient intake and sarcopenia in RA.MethodsA prospective cohort study with follow‐up for 1 year examined body composition and diet in female outpatients with RA. We performed logistic regression analysis to assess which factors might have contributed to this loss of muscle mass. Multivariate logistic regression analysis with a forward–backward stepwise selection was also analysed. SKG/Jcl mice, which develop RA spontaneously, were fed normal chow or a high‐fat diet (HFD) and evaluated for inflammation and muscle mass.ResultsA total 53 female patients were included. The median age was 57.0 years, with an interquartile range (IQR) of 49.5 to 62.0 years, and the median disease duration was 4.0 years, with an IQR of 2.0 to 9.0 years. Fourteen patients (26.4%) had skeletal muscle mass index below the cut‐off for sarcopenia (≤5.7 kg/m2) as defined by the Asia Working Group for Sarcopenia. Multiple logistic regression analysis revealed that the intake of saturated fatty acids was associated with a >5% decrease in skeletal muscle index of RA patients over 1 year [odds ratio 95% confidence interval 1.431 (1.082–1.894), P = 0.012]. In 9 weeks old SKG/Jcl mice, HFD feeding precipitated the onset of RA and exacerbated rheumatoid synovitis in association with the induction of T helper 17 cell differentiation. The serum concentrations of inflammatory cytokines including IL‐6 and TNF‐α were significantly higher in HFD‐fed RA mice than in normal chow (NC)‐fed RA mice or in HFD‐fed control mice (IL‐6; 3.8 vs. 32.2 pg/mL, P < 0.05). Moreover, the HFD increased expression of the genes for the ubiquitin ligases atrogin‐1 and muscle‐specific RING‐finger protein‐1 (MuRF‐1) in skeletal muscle and elicited a marked loss of muscle mass in these mice (atrogin‐1; 1.72‐fold, MuRF‐1; 1.24‐fold in HFD‐fed mice). HFD‐fed RA mice showed a significant decrease in the weight of gastrocnemius and extensor digitorum longus and muscle volume of the lower limbs compared with NC‐fed RA mice or HFD‐fed control mice at 14 weeks of age.ConclusionsOur findings suggest that the consumption of saturated fat may be related to muscle loss in RA patients, and they may therefore provide a basis for a new dietary intervention strategy to prevent muscle wasting associated with this disease.

Abstract BackgroundThe interaction between the muscle methylome and transcriptome is understudied during ageing and periods of resistance training in young, but especially older adults. More information is needed on the role of retained methylome training adaptations in muscle memory to understand muscle phenotypical and molecular restoration after inactivity or disuse.MethodsWe measured CpG methylation (microarray) and RNA expression (RNA sequencing) in young (n = 5; age = 22 ± 2 years) and older (n = 6; age = 65 ± 5 years) vastus lateralis muscle samples, taken at baseline, after 12 weeks of resistance training, after training interruption (2 weeks of leg immobilization in young men, 12 weeks of detraining in older men) and after 12 weeks of retraining to identify muscle memory‐related adaptations and rejuvenating effects of training.ResultsWe report that of the 427 differentially expressed genes with advanced age (FDR < 0.1), 71% contained differentially methylated (dm)CpGs in older versus young muscle (FDR < 0.1, M‐value difference >0.4). The more dmCpGs within a gene, the clearer the inverse methylation–expression relationship. Around 73% of the age‐related dmCpGs approached younger methylation levels when older muscle was trained for 12 weeks. A second resistance training period after training cessation increased the number of hypomethylated CpGs and upregulated genes in both young and older muscle. We found indication for an epi‐memory within pro‐proliferating AMOTL1 in young muscle and mechanosensing‐related VCL in older muscle. For the first time, we integrate muscle methylome and transcriptome data in relation to both ageing and training‐induced/inactivity‐induced responses and identify focal adhesion as an important pathway herein.ConclusionsThis preliminary evidence indicates that previously trained muscle is more responsive to training than untrained muscle at methylome and transcriptome level and recurrent resistance training can partially restore ageing‐induced methylome alterations.

Abstract BackgroundPhysical activity is associated with a lower risk of colorectal cancer (CRC) and CRC‐specific mortality. However, evidence for a causal relationship between physical activity and disease progression is lacking. Here, we have used CRC organoids to create a novel mouse model for spontaneous metastasis formation to multiple organs. We have used this model to assess the influence of voluntary exercise on disease progression.MethodsCollagen‐embedded murine colorectal tumour organoids were transplanted into the livers of immunocompetent C57Bl/6 mice using microsurgery. Voluntary exercise in tumour‐bearing mice was modelled by offering running wheels continuously (n = 12) or 3 h/day (n = 12) versus no wheel access (n = 12). Running wheel revolutions were cumulatively measured every 30 min and physical activity was continuously monitored by infrared cameras. Food intake was monitored throughout the experiment and body composition was assessed with echoMRI. Animals were sacrificed 14 weeks after tumour initiation. Tumour load was quantified by EpCAM immunohistochemistry staining. Systemic inflammation parameters were assessed in blood plasma by a multiplex immunoassay.ResultsTumour growth was initiated by implantation of CRC organoids into the livers of immunocompetent mice. The resulting tumours spontaneously formed distant metastases to non‐implanted liver lobes and to the lungs. Mice with access to the running wheels for 3 h/day ran relatively short distances (2.3 ± 0.3 km/night; 221 ± 29 km total distance) with relatively high intensity (wheel revolutions/h). Mice with continuous access to the running wheels ran significantly longer distances (6.6 ± 3.0 km/night; 600 ± 290 km total distance) with a significantly lower intensity. Both exercise groups showed increased lean body mass, and decreased fat mass and body weight compared with tumour‐bearing control mice. Food intake was unaffected by exercise or tumour growth. Primary tumour growth was not significantly affected by exercise. However, mice with continuous wheel access (long distance‐lower intensity group) displayed increased lung metastasis and decreased liver metastasis formation, when compared with the sedentary control group. Short distance‐higher intensity exercise did not affect metastasis formation. Analysis of blood cytokine levels revealed that mice with continuous wheel access displayed signs of systemic inflammation.ConclusionsThese results suggest that exercise has the potential to influence the patterns and extent of metastasis in CRC, and that the degree and intensity of exercise are likely to be important variables. Confirmation of these results in additional preclinical models with or without systemic treatment is warranted.

Abstract BackgroundThe chronic nature of congenital heart diseases (CHDs) leads to the activation of inflammatory and neurohormonal processes in the body, and there is a possibility of the occurrence of other complications such as sarcopenia. The aim of the present study was to evaluate sarcopenia prevalence in adult patients with CHDs.MethodsBetween April 2017 and December 2019, the current investigation recruited 85 patients from those referring to the Outpatient Adult CHD Clinic. Dual‐energy X‐ray absorptiometry (DXA) was employed to determine body composition and muscle mass. Handgrip strength is usually used to measure muscle strength. The 6‐min walk test (6MWT) and the 4‐m gait speed (4MGS) test were used for the evaluation of muscle performance. The presence of sarcopenia was defined based on the European Working Group on Sarcopenia in Older People.ResultsThe study patients (44.7% male) were aged between 16 and 48 years. More than half of them (48 [56.5%] patients) were classified as severe complex CHDs. Most of the patients (73%) were asymptomatic. The diagnostic criteria of sarcopenia were fulfilled by 24 (28.2%) patients, whereas 15 patients fulfilled two criteria and nine patients met all three criteria for sarcopenia. According to the diagnostic criteria, 32.9% of patients had only a decreased skeletal muscle and considered as pre‐sarcopenia. Sarcopenia was more frequent in female patients (P = 0.02), patients with severe complex CHDs (P = 0.03), those with arterial desaturation (P = 0.001), ones with Eisenmenger syndrome (P = 0.002) and those without a history of corrective interventions (P = 0.03). The 6MWT measure was significantly reduced in the patients with sarcopenia (P < 0.0001). The patients with sarcopenia had also higher haemoglobin and haematocrit levels (P < 0.0001). Logistic regression multivariate analysis showed that the body mass index, haematocrit and 6MWT distance could be independently associated with sarcopenia in our study population.ConclusionsThe present study showed that adult patients with complex CHDs have impaired muscle strength and reduced muscle mass with a high prevalence of sarcopenia in spite of their young age.

Abstract BackgroundCachexia is a debilitating complication of cancer characterized by progressive wasting and weakness of skeletal muscles that reduces quality of life and can compromise survival. Many anticancer treatments, such as chemotherapy, also cause muscle wasting, which impairs the response to treatment. Given that many cancer patients present with cachexia at the initiation of treatment, we investigated whether cachectic mice were susceptible to chemotherapy‐induced muscle wasting and to investigate contributing mechanisms, including the dysregulation of microRNAs (miRs).MethodsCachectic colon‐26 (C‐26) tumour‐bearing mice were given 5‐fluourouracil (5‐FU) chemotherapy or vehicle treatment and analysed for muscle mass, fibre size and composition, and miR expression. Mechanisms were validated in vitro using C2C12 cell culture and miR mimics and inhibitors and were confirmed in vivo by injecting muscles of 5‐FU‐treated cachectic mice with recombinant adeno‐associated viral (rAAV) vectors encoding a miR sponge.ResultsIn cachectic tumour‐bearing mice, 5‐FU chemotherapy exacerbated the loss of skeletal muscle mass compared with vehicle treatment (by −12% to −20%, P < 0.05). miR expression profiling, quantitative real‐time PCR, and in vitro analyses revealed contributing mechanisms including miR‐351‐3p‐dependent ERK2 inhibition. Intramuscular injection of rAAV vectors encoding a sponge to reduce miR‐351‐3p expression in 5‐FU‐treated cachectic mice enhanced ERK phosphorylation (+18%, P < 0.05) and increased muscle fibre size (+15%, P < 0.01). Hsa‐miR‐125a‐3p shares similar predicted gene targets as mmu‐miR‐351‐3p, and its inhibition in human muscle cells in vitro prevented 5‐FU‐induced atrophy (P < 0.001) and increased ERK phosphorylation (P < 0.001).ConclusionsThe findings implicate miR‐351‐3p‐mediated ERK2 inhibition as a contributing mechanism in chemotherapy‐induced muscle wasting in mice with cancer cachexia and that its inhibition is a promising adjunct therapy for preserving muscles during cancer treatment.