Alternative lengthening of telomeres (ALT) is a telomere elongation mechanism activated during oncogenesis and primarily acting in tumors of mesenchymal origin. Although the proteins involved in the machinery enabling ALT to elongate telomeres are becoming better understood, the underlying biology of this mechanism remains unclear. In the present study, we took advantage of a fully characterized cohort of 98 leiomyosarcomas (LMS) from the French Sarcoma Group to further our understanding of the ALT mechanism. We first compared the transcriptomic profiles of ALT+ and TERT+ LMS and demonstrated a strong enrichment of the CINSARC signature in ALT+ tumors. The establishment of an ALT+-related signature in these LMS confirmed the close association between CINSARC and ALT in two additional cohorts of non-translocation-related sarcomas. In vitro mesenchymal models of spontaneous ALT induction showed increased CINSARC expression following acquisition of the ALT mechanism. Conversely, ALT inactivation, through BLM inhibition, led to decreased CINSARC expression. These results establish CINSARC as a new hallmark of the ALT mechanism in non-translocation-related sarcomas and demonstrate the association of a cellular biological process with the CINSARC prognostic signature, namely the ALT mechanism.

Chronic obstructive pulmonary disease (COPD) is a respiratory disease with systemic complications, including vascular dysfunction. Aerobic exercise improves blood pressure, endothelial function, and muscle angiogenesis in health and disease, but these effects in COPD are inconsistent. The elastase and lipopolysaccharide (LPS)-induced emphysema (ELA-LPS) model with exacerbation replicates COPD cardiovascular comorbidities. We aimed to assess the impact of aerobic exercise on blood pressure and endothelial determinants in this model. Male Wistar rats were assigned to four groups: controls (Ctrl), controls with exercise (Ctrl + Ex), emphysema (ELA-LPS), and emphysema with exercise (ELA-LPS + Ex). After 4 wk of treadmill training, we assessed respiratory parameters, maximal oxygen consumption (V̇o2max), heart rate, systolic/diastolic/mean arterial pressures, skeletal muscle capillarization, and ex vivo vascular reactivity. At baseline, compared with Ctrl, ELA-LPS animals exhibited reduced V̇o2max, elevated blood pressure, and enhanced endothelium-dependent vasorelaxation via cyclooxygenase-dependent pathways. Aerobic exercise increased exercise capacity, lowered heart rate (HR), and reduced blood pressure (BP) in both groups. In Ctrl + Ex, aerobic exercise enhanced endothelium-dependent relaxation through nitric oxide (NO) signaling and increased muscle capillarization. In contrast, in ELA-LPS + Ex, aerobic exercise did not further increased vasorelaxation, although NO dependence of the endothelium-dependent relaxation was restored and no increase in muscle capillarization was observed. Aerobic exercise training improved HR and BP in emphysema but failed to fully restore microvascular adaptations, suggesting disease-specific vascular remodeling. These findings highlight a complex interplay between training-induced and disease-induced vascular changes. Clinical studies are warranted to define vascular phenotypes of patients with COPD responsive to aerobic exercise-induced blood pressure reduction.NEW & NOTEWORTHY Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular comorbidities, but the vascular benefits of exercise remain uncertain. In an elastase-LPS rat model of COPD with preexisting vascular adaptations, aerobic training improves exercise capacity and lowers blood pressure but does not further enhance vascular reactivity or angiogenesis. Pathological vascular adaptations in COPD may interfere with the vascular benefits of aerobic training.

Chronic obstructive pulmonary disease (COPD) is frequently associated with skeletal muscle dysfunction, having a considerable impact on exercise tolerance and patient prognosis. Mitochondria play a role in skeletal muscle weakness and exercise intolerance in COPD, but the majority of studies on mitochondrial function are biased by the fact that physical activity is greater in healthy subjects than in patients. Furthermore, exercise training (ET) has been proposed as a therapeutic strategy to prevent skeletal muscle dysfunction in COPD, but very few results are available on mitochondrial adaptation in response to ET. Skeletal muscle mitochondrial function and the potential efficacy of ET on this function were compared between 12 patients with COPD and 21 healthy subjects with similar low levels of physical activity. Various markers of mitochondrial respiration, oxidative stress, biogenesis, and dynamics were assessed. Lower oxidative phosphorylation (OxPhos; p < 0.001) and increased nonphosphorylating respiration (p = 0.025) and mitochondrial oxidative damage (lipid peroxidation (p = 0.014) and protein carbonylation (p = 0.020)) were observed in patients. While ET increased OxPhos efficiency (p = 0.011) and reduced nonphosphorylating respiration (p < 0.001) and lipid peroxidation (p < 0.001) in patients' muscle mitochondria, it fails to improve maximal respiration (p = 0.835) and expression of the antioxidant enzyme MnSOD (p = 0.606), mitochondrial transcription factor TFAM (p = 0.246), and mitochondrial complexes I, III, and IV (p = 0.816, p = 0.664, p = 0.888, respectively) as observed in healthy subjects. The mitochondrial dysfunction and the defects in mitochondrial adaptation to ET that we observe in the muscle of patients with COPD are intrinsic to the disease and do not arise from muscle disuse.

Dedifferentiated and Well-differentiated liposarcoma are characterized by a systematic amplification of the Murine Double Minute 2 (MDM2) oncogene. We demonstrate that p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in liposarcoma and mediate an addiction to serine metabolism to sustain tumor growth. However, the origin of exogenous serine remains unclear. Here, we show that elevated serine levels in mice harboring liposarcoma-patient derived xenograft, released by distant muscle is essential for liposarcoma cell survival. Repressing interleukine-6 expression, or treating liposarcoma cells with Food and Drugs Administration (FDA) approved anti-interleukine-6 monoclonal antibody, decreases de novo serine synthesis in muscle, impairs proliferation, and increases cell death in vitro and in vivo. This work reveals a metabolic crosstalk between muscle and liposarcoma tumor and identifies anti-interleukine-6 as a plausible treatment for liposarcoma patients.

AIMS/HYPOTHESIS:Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications. METHODS:Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells. RESULTS:Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes. CONCLUSIONS/INTERPRETATION:These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity.

AIM:Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction and development of emphysema. Among the comorbidities associated with COPD, skeletal muscle dysfunction is known to affect exercise capacity and the survival rate of patients. Pulmonary rehabilitation (PR), via exercise training, is essential for COPD patients. However, the response to PR is most often moderate. An animal model that recapitulates critical features of chronic human disease and provides access to muscle function should therefore be useful to improve PR benefits. METHODS:We used a rat model of induced emphysema based on pulmonary instillations of elastase (ELA) and lipopolysaccharides (LPS). We assessed the long-term effects of ELA/LPS and the potential effectiveness of endurance training on the skeletal muscle function. In vivo strength of the animals, and ex vivo contractility, endurance, type 1 fiber proportion, fiber cross-sectional area, and capillarization of both soleus and extensor digitorum longus (EDL) were assessed. RESULTS:An impaired overall muscle strength with decreased force, reduced capillarization, and atrophy of type 1 fiber of EDL was observed in ELA/LPS rats. Soleus was not affected. Endurance training was able to reduce fatigability, and increase type 1 fiber proportion and capillarization of soleus, and improve force, endurance, and capillarization of EDL in control and ELA/LPS rats. CONCLUSION:Our rat model of induced emphysema, which shares some features with the phenotype present in patients with COPD, could represent a suitable model to study skeletal muscle dysfunction and the effects of exercise training on muscle function in patients.

Skeletal muscle wasting, whether related to physiological ageing, muscle disuse or to an underlying chronic disease, is a key determinant to quality of life and mortality. However, cellular basis responsible for increased catabolism in myocytes often remains unclear. Although myocytes represent the vast majority of skeletal muscle cellular population, they are surrounded by numerous cells with various functions. Animal models, mostly rodents, can help to decipher the mechanisms behind this highly dynamic process, by allowing access to every muscle as well as time-course studies. Satellite cells (SCs) play a crucial role in muscle regeneration, within a niche also composed of fibroblasts and vascular and immune cells. Their proliferation and differentiation is altered in several models of muscle wasting such as cancer, chronic kidney disease or chronic obstructive pulmonary disease (COPD). Fibro-adipogenic progenitor cells are also responsible for functional muscle growth and repair and are associated in disease to muscle fibrosis such as in chronic kidney disease. Other cells have recently proven to have direct myogenic potential, such as pericytes. Outside their role in angiogenesis, endothelial cells and pericytes also participate to healthy muscle homoeostasis by promoting SC pool maintenance (so-called myogenesis-angiogenesis coupling). Their role in chronic diseases muscle wasting has been less studied. Immune cells are pivotal for muscle repair after injury: Macrophages undergo a transition from the M1 to the M2 state along with the transition between the inflammatory and resolutive phase of muscle repair. T regulatory lymphocytes promote and regulate this transition and are also able to activate SC proliferation and differentiation. Neural cells such as terminal Schwann cells, motor neurons and kranocytes are notably implicated in age-related sarcopenia. Last, newly identified cells in skeletal muscle, such as telocytes or interstitial tenocytes could play a role in tissular homoeostasis. We also put a special focus on cellular alterations occurring in COPD, a chronic and highly prevalent respiratory disease mainly linked to tobacco smoke exposure, where muscle wasting is strongly associated with increased mortality, and discuss the pros and cons of animal models versus human studies in this context. Finally, we discuss resident cells metabolism and present future promising leads for research, including the use of muscle organoids.

Background Obstructive sleep apnea syndrome is a common sleep-breathing disorder associated with adverse health outcomes including excessive daytime sleepiness, impaired quality of life and is well-established as a cardiovascular risk factor. Continuous positive airway pressure is the reference treatment, but its cardiovascular and metabolic benefits are still debated. Combined interventions aiming at improving patient's lifestyle behaviours are recommended in guidelines management of obstructive sleep apnea syndrome but adherence decreases over time and access to rehabilitation programmes is limited. Telerehabilitation is a promising approach to address these issues, but data are scarce on obstructive sleep apnea syndrome. Methods The aim of this study is to assess the potential benefits of a telerehabilitation programme implemented at continuous positive airway pressure initiation, compared to continuous positive airway pressure alone and usual care, on symptoms and cardiometabolic risk factors of obstructive sleep apnea syndrome. This study is a 6-months multicentre randomized, parallel controlled trial during which 180 obese patients with severe obstructive sleep apnea syndrome will be included. We will use a sequential hierarchical criterion for major endpoints including sleepiness, quality of life, nocturnal systolic blood pressure and inflammation biological parameters. Discussion m-Rehab obstructive sleep apnea syndrome is the first multicentre randomized controlled trial to examine the effectiveness of a telerehabilitation lifestyle programme in obstructive sleep apnea syndrome. We hypothesize that a telerehabilitation lifestyle intervention associated with continuous positive airway pressure for 6 months will be more efficient than continuous positive airway pressure alone on symptoms, quality of life and cardiometabolic risk profile. Main secondary outcomes include continuous positive airway pressure adherence, usability and satisfaction with the telerehabilitation platform and medico-economic evaluation. Trial registration Clinicaltrials.gov Identifier: NCT05049928. Registration data: 20 September 2021

Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients’ samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.

Abstract Background Beta‐alanine (BA) supplementation increases muscle carnosine, an abundant endogenous antioxidant and pH buffer in skeletal muscle. Carnosine loading promotes exercise capacity in healthy older adults. As patients with chronic obstructive pulmonary disease (COPD) suffer from elevated exercise‐induced muscle oxidative/carbonyl stress and acidosis, and from reduced muscle carnosine stores, it was investigated whether BA supplementation augments muscle carnosine and induces beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress in patients with COPD. Methods In this double‐blind, randomized, placebo (PL)‐controlled trial (clinicaltrials.gov identifier: NCT02770417), 40 patients (75% male) with COPD (mean ± standard deviation: age 65 ± 6 years; FEV1% predicted 55 ± 14%) were assigned to 12 weeks oral BA or PL supplementation (3.2 g/day). The primary outcome, i.e. muscle carnosine, was quantified from m. vastus lateralis biopsies obtained before and after intervention. Co‐primary outcomes, i.e. incremental and constant work rate cycle capacity, were also assessed. Linear mixed model analyses were performed. Compliance with and side effects of supplement intake and secondary outcomes (quadriceps strength and endurance, and muscle oxidative/carbonyl stress) were also assessed. Results Beta‐alanine supplementation increased muscle carnosine in comparison with PL in patients with COPD (mean difference [95% confidence interval]; +2.82 [1.49–4.14] mmol/kg wet weight; P < 0.001). Maximal incremental cycling capacity (VO2peak: +0.5 [−0.7 to 1.7] mL/kg/min; P = 0.384, Wpeak: +5 [−1 to 11] W; P = 0.103) and time to exhaustion on the constant work rate cycle test (+28 [−179 to 236] s; P = 0.782) did not change significantly. Compliance with supplement intake was similar in BA (median (quartile 1–quartile 3); 100 (98–100)%) and PL (98 (96–100)%) (P = 0.294) groups, and patients did not report side effects possibly related to supplement intake. No change was observed in secondary outcomes. Conclusions Beta‐alanine supplementation is efficacious in augmenting muscle carnosine (+54% from mean baseline value) without side effects in patients with COPD in comparison with PL. However, accompanied beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress were not observed.

Carnosine, particularly present in fast-twitch fibers, was investigated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD). Carnosine concentration was similar between patients with COPD and healthy controls but was 30% lower in patients with severe/very severe COPD, despite their high proportion of fast-twitch fibers, versus patients with mild/moderate COPD. As no oxidative/carbonyl stress markers or antioxidants were affected, the observed carnosine deficiency is thought to be a possible first sign of muscle redox balance abnormalities.

Skeletal muscle dysfunction is a common characteristic of the lower limbs of Chronic Obstructive Pulmonary Disease (COPD) patients, and is known to affect the quality of life and survival rate of patients. While a complex interplay of systemic and intrinsic factors has been advanced to explain this dysfunction, the involvement of an altered Ca2+-dependent contractility of muscle cells in patients with COPD has not been extensively studied. Our aim was to assess whether intracellular Ca2+ regulation was altered in COPD myotubes compared to healthy myotubes. Myotubes from 9 healthy subjects (FEV1%: 102.4±14.7%) or 9 COPD patients (FEV1%: 36.3±14.6%) loaded with the Ca2+-sensitive dye Fura-2 were subjected to KCl-induced depolarization. Using fluorescence microscopy, intracellular resting Ca2+ and KCl-induced Ca2+ responses were assessed in 60 myotubes per subject. We found that intracellular resting Ca2+ was similar in non-stimulated healthy and COPD myotubes. Upon KCl stimulation, the intracellular Ca2+ increase (-45.3%, p<0.0001), peak (-41.3%, p=0.004) and decrease (-43.4%, p=0.002) were reduced in COPD myotubes. The Ca2+ response was positively correlated to endurance and resistance parameters of the subjects (6-minute walking distance [%th], p=0.002; quadriceps maximum voluntary contraction [kg], p=0.022). Compared to healthy myotubes, COPD myotubes show a reduced Ca2+ response to KCl-induced depolarization that could reflect an altered contractility of the COPD myotubes leading to the in vivo muscle dysfunction in COPD patients.

Among the comorbidities associated with chronic obstructive pulmonary disease (COPD), skeletal muscle weakness and atrophy are known to affect patient survival rate. In addition to muscle deconditioning, various systemic and intrinsic factors have been implicated in COPD muscle dysfunction but an impaired COPD muscle adaptation to contraction has never been extensively studied. We submitted cultured myotubes from nine healthy subjects and nine patients with COPD to an endurance-type protocol of electrical pulse stimulation (EPS). EPS induced a decrease in the diameter, covered surface and expression of MHC1 in COPD myotubes. Although the expression of protein degradation markers was not affected, expression of the protein synthesis marker mTOR was not induced in COPD compared to healthy myotubes after EPS. The expression of the differentiation markers p16INK4a and p21 was impaired, while expression of Myf5 and MyoD tended to be affected in COPD muscle cells in response to EPS. The expression of mitochondrial biogenesis markers PGC1α and MFN2 was affected and expression of TFAM and COX1 tended to be reduced in COPD compared to healthy myotubes upon EPS. Lipid peroxidation was increased and the expression of the antioxidant enzymes SOD2 and GPx4 was affected in COPD compared to healthy myotubes in response to EPS. Thus, we provide evidence of an impaired response of COPD muscle cells to contraction, which might be involved in the muscle weakness observed in patients with COPD.

BACKGROUND AND OBJECTIVES:Age and comorbidity-related sarcopenia represent a main cause of muscle dysfunction in patients on long-term hemodialysis. However, recent findings suggest muscle abnormalities that are not associated with sarcopenia. The aim of this study was to isolate functional and cellular muscle abnormalities independently of other major confounding factors, including malnutrition, age, comorbidity, or sedentary lifestyle, which are common in patients on maintenance hemodialysis. To overcome these confounding factors, alterations in skeletal muscle were analyzed in highly selected patients on long-term hemodialysis undergoing kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:In total, 22 patients on long-term hemodialysis scheduled for kidney transplantation with few comorbidities, but with a long-term uremic milieu exposure, and 22 age, sex, and physical activity level frequency-matched control participants were recruited. We compared biochemical, functional, and molecular characteristics of the skeletal muscle using maximal voluntary force and endurance of the quadriceps, 6-minute walking test, and muscle biopsy of vastus lateralis. For statistical analysis, mean comparison and multiple regression tests were used. RESULTS:In patients on long-term hemodialysis, muscle endurance was lower, whereas maximal voluntary force was not significantly different. We observed a transition from type I (oxidative) to type II (glycolytic) muscle fibers, and an alteration of mitochondrial structure (swelling) without changes in DNA content, genome replication (peroxisome proliferator activator receptor γ coactivator-1α and mitochondrial transcription factor A), regulation of fusion (mitofusin and optic atrophy 1), or fission (dynamin-related protein 1). Notably, there were autophagosome structures containing glycogen along with mitochondrial debris, with a higher expression of light chain 3 (LC3) protein, indicating phagophore formation. This was associated with a greater conversion of LC3-I to LC3-II and the expression of Gabaralp1 and Bnip3l genes involved in mitophagy. CONCLUSIONS:In this highly selected long-term hemodialysis population, a low oxidative phenotype could be defined by a poor endurance, a fiber-type switch, and an alteration of mitochondria structure, without evidence of sarcopenia. This phenotype could be related to uremia through the activation of autophagy/mitophagy. CLINICAL TRIAL REGISTRATION NUMBERS:NCT02794142 and NCT02040363.

Background: Beta-alanine (BA) supplementation increases muscle carnosine (mCAR), an endogenous antioxidant and pH-buffer. It may be a strategy to enhance exercise capacity in patients with COPD as they suffer from elevated exercise-induced muscle oxidative stress and acidosis. We investigated whether BA supplementation increases mCAR and induces change in oxidative/carbonyl stress, antioxidants and physical capacity in patients with COPD. Methods: In a double blind, placebo(PL)-controlled, randomized trial, 40 patients (65±6 y; 75% male; 55±14 FEV1%pred) were assigned to 12 weeks oral BA or PL. Biopsy of m. vastus lateralis was obtained pre/post intervention and mCAR, proteins affected by carbonylation and 4-hydroxynonenal, and mRNA expression of antioxidants were quantified. Incremental and constant work-rate cycle capacity, and quadriceps strength and endurance were assessed. Linear mixed model analysis was performed. Results: BA supplementation increased mCAR and reduced mRNA expression of glutathione peroxidase 4 (GPX4) vs. PL, while oxidative/carbonyl stress, other antioxidants and physical capacity did not change (Table 1). Conclusion: BA supplementation augments mCAR with 54% of baseline values in patients with COPD, which seems to downregulate antioxidant GPX4, but not beneficially change oxidative/carbonyl stress, other antioxidants and physical capacity.

Background Pulmonary rehabilitation (PR) improves exercise capacity, health-related quality of life (HRQoL) and dyspnea in chronic obstructive pulmonary disease (COPD) patients. Maintenance programs can sustain the benefits for 12 to 24 months. Yet, the long-term effects (> 12 months) of pragmatic maintenance programs in real-life settings remain unknown. This prospective cohort study assessed the yearly evolution in the outcomes [6-min walking distance (6MWD), HRQoL, dyspnea] of a supervised self-help PR maintenance program for COPD patients followed for 5 years. The aim was to assess the change in the outcomes and survival probability for 1 to 5 years after PR program discharge in COPD patients following a PR maintenance program supported by supervised self-help associations. Methods Data were prospectively collected from 144 COPD patients who followed a pragmatic multidisciplinary PR maintenance program for 1 to 5 years. They were assessed yearly for 6MWD, HRQol (VQ11) and dyspnea (MRC). The 5-year survival probability was compared to that of a control PR group without a maintenance program. A trajectory-based cluster analysis identified the determinants of long-term response. Results Maintenance program patients showed significant PR benefits at 4 years for 6MWD and VQ11 and 5 years for MRC. The 5-year survival probability was higher than for PR patients without PR maintenance. Two clusters of response to long-term PR were identified, with responders being the less severe COPD patients. Conclusions This study provides evidence of the efficacy of a pragmatic PR maintenance program in a real-life setting for more than 3 years. In contrast to short-term PR, long-term PR maintenance appeared more beneficial in less severe COPD patients.

Background Obesity is a major public health issue. Combining exercise training, nutrition, and therapeutic education in metabolic rehabilitation (MR) is recommended for obesity management. However, evidence from randomized controlled studies is lacking. In addition, MR is associated with poor patient adherence. Mobile health devices improve access to MR components. Objective The aim of this study is to compare the changes in body composition, anthropometric parameters, exercise capacity, and quality of life (QOL) within 12 weeks of patients in the telerehabilitation (TR) program to those of usual care patients with obesity. Methods This was a parallel-design randomized controlled study. In total, 50 patients with obesity (BMI>30 kg/m²) were included in a TR group (TRG) or a usual care group (UCG) for 12 weeks. Patients underwent biometric impedance analyses, metabolic exercise tests, actimetry, and QOL and satisfaction questionnaires. The primary outcome was the change in fat mass at 12 weeks from baseline. Secondary outcomes were changes in body weight, metabolic parameters, exercise capacity, QOL, patients’ adhesion, and satisfaction. Results A total of 49 patients completed the study. No significant group × time interaction was found for fat mass (TRG: mean 1.7 kg, SD 2.6 kg; UCG: mean 1.2 kg, SD 2.4 kg; P=.48). Compared with the UCG, TRG patients tended to significantly improve their waist to hip ratios (TRG: −0.01 kg, SD 0.04; UCG: +0.01 kg, SD 0.06; P=.07) and improved QOL physical impact (TRG: +21.8, SD 43.6; UCG: −1.2, SD 15.4; P=.005). Significant time effects were observed for body composition, 6-minute walk test distance, exercise metabolism, sedentary time, and QOL. Adherence (95%) and satisfaction in the TRG were good. Conclusions In adults with obesity, the TR program was not superior to usual care for improving body composition. However, TR was able to deliver full multidisciplinary rehabilitation to patients with obesity and improve some health outcomes. Given the patients’ adherence and satisfaction, pragmatic programs should consider mobile health devices to improve access to MR. Further studies are warranted to further establish the benefits that TR has over usual care. Trial Registration ClinicalTrials.gov NCT03396666; http://clinicaltrials.gov/ct2/show/NCT03396666

Myogenic differentiation mechanisms are generally assessed using a murine cell line placed in low concentrations of an animal-derived serum. To more closely approximate in vivo pathophysiological conditions, recent studies have combined the use of human muscle cells with human serum. Nevertheless, the in vitro studies of the effects of a human microenvironment on the differentiation process of human myoblasts require the identification of the culture conditions that would provide an optimal and reproducible differentiation process of human muscle cells. We assessed the differentiation variability resulting from the use of human myoblasts and serums from healthy subjects by measuring the myotube diameter, fusion index and surface covered by myotubes. We showed the preserved cell-dependent variability of the differentiation response of myoblasts cultured in human serums compared to FBS. We found that using a pool of serums reduced the serum-dependent variability of the myogenic response compared to individual serums. We validated our methodology by showing the atrophying effect of pooled serums from COPD patients on healthy human myotubes. By replacing animal-derived tissues with human myoblasts and serums, and by validating the sensitivity of cultured human muscle cells to a pathological microenvironment, this human cell culture model offers a valuable tool for studying the role of the microenvironment in chronic disease.

This work confirms the previously reported impairment in the functional response to exercise training of patients with COPD compared with SHS. Moreover, it shows for the first time that pericyte coverage of the skeletal capillaries is drastically reduced in patients with COPD compared with SHS during training-induced angiogenesis. Finally, it provides experimental evidence that circulating factors are involved in the impaired pericyte coverage of patients with COPD.

Exercise training (ET) is a major part of pulmonary rehabilitation for Chronic Obstructive Pulmonary Disease (COPD) patients. However, ET for COPD patients has limited beneficial effects on peripheral muscles. Our objective was to assess the cellular mechanisms that could lead to the limited beneficial effects of ET in COPD using in vitro Electrical Pulse Stimulation (EPS) of cultured human myotubes. Myotubes from 9 healthy subjects (FEV1%: 102.4±14.7%) or 9 COPD patients (FEV1%: 36.3±14.6%) were subjected to an EPS protocol during 24 hours at 1 Hz and 11.5 V. We compared the variations (EPS - noEPS) of the myotube diameter, surface covered by myotubes, fusion index, and expression of differentiation, catabolic, anabolic and oxidative metabolism markers in healthy and COPD myotubes. EPS induced an increase of the differentiation characteristics (diameter +3.8 vs -4.6%; surface +4.5 vs -5.3%; fusion +4.4 vs -4.9%; p<0.05), and of myogenesis (MyoD +19.3 vs -4.2%; p<0.05), protein synthesis (mTOR +29.7 vs +0.9%; p<0.05) and oxidative metabolism (MHC1 +20.8 vs -10.1%; PGC1α +126.0 vs +49.7%; p<0.05) markers in healthy myotubes. No difference was observed for catabolic markers MuRF1and atrogin1. We showed that, unlike healthy myotubes, COPD myotubes have a limited response to EPS with alteration of differentiation, protein synthesis and oxidative metabolism adaptation. This altered response to EPS in vitro could reflect impaired regenerative capacities of satellite cells leading to a lack of muscle adaptation and therefore to the limited effects of in vivo ET in COPD patients.