Reduction In Lean Mass Research Articles

TRIM16 facilitates SIRT-1-dependent regulation of antioxidant response to alleviate age-related sarcopenia.

Age-related sarcopenia, characterized by reduced skeletal muscle mass and function, significantly affects the health of the elderly individuals. Oxidative stress plays a crucial role in the development of sarcopenia. Tripartite motif containing 16 (TRIM16) is implicated in orchestrating antioxidant responses to mitigate oxidative stress, yet its regulatory role in skeletal muscle remains unclear. This study aims to elucidate the impact of TRIM16 on enhancing antioxidant response through SIRT-1, consequently mitigating age-related oxidative stress, and ameliorating muscle atrophy. Aged mouse models were established utilizing male mice at 18months with D-galactose (D-gal, 200mg/kg) intervention and at 24months with natural aging, while 3-month-old young mice served as controls. Muscle cell senescence was induced in C2C12 myoblasts using 30g/L D-gal. TRIM16 was overexpressed in the skeletal muscle of aged mice and silenced/overexpressed in C2C12 myoblasts. The effects of TRIM16 on skeletal muscle mass, grip strength, morphological changes, myotube formation, myogenic differentiation, and muscle atrophy indicators were evaluated. Reactive oxygen species (ROS) levels and oxidative stress-related parameters were measured. The SIRT-1 inhibitor EX-527 was employed to elucidate the protective role of TRIM16 mediated through SIRT-1. Aged mice displayed significant reductions in lean mass (-11.58%; -14.47% vs. young, P<0.05), hindlimb lean mass (-17.38%; -15.95% vs. young, P<0.05), and grip strength (-22.29%; -31.45% vs. young, P<0.01). Skeletal muscle fibre cross-sectional area (CSA) decreased (-29.30%; -24.12% vs. young, P<0.05). TRIM16 expression significantly decreased in aging skeletal muscle (-56.82%; -66.27% vs. young, P<0.001) and senescent muscle cells (-46.53% vs. control, P<0.001). ROS levels increased (+69.83% vs. control, P<0.001), and myotube formation decreased in senescent muscle cells (-56.68% vs. control, P<0.001). Expression of myogenic differentiation and antioxidant indicators decreased, while muscle atrophy markers increased in vivo and in vitro (all P<0.05). Silencing TRIM16 in myoblasts induced oxidative stress and myotube atrophy, while TRIM16 overexpression partially mitigated aging effects on skeletal muscle. TRIM16 activation enhanced SIRT-1 expression (+75.38% vs. control, P<0.001). SIRT-1 inhibitor EX-527 (100μM) suppressed TRIM16's antioxidant response and mitigating muscle atrophy, offsetting the protective effect of TRIM16 on senescent muscle cells. This study elucidates TRIM16's role in mitigating oxidative stress and ameliorating muscle atrophy through the activation of SIRT-1-dependent antioxidant effects. TRIM16 emerges as a potential therapeutic target for age-related sarcopenia.

Effects of Exercise Type on Muscle Strength and Body Composition in Men and Women: A Systematic Review and Meta-Analysis.

Background and Objectives: There are typical differences in body composition and distribution of muscle fiber types between women and men. However, research investigating the effects of exercise based on sex differences is limited, and studies examining sex differences in physiological adaptations according to exercise type are scarce. We aimed to compare the effects of exercise types on muscle strength and body composition in men and women through a meta-analysis. Materials and Methods: A systematic literature search was conducted using the PubMed/Medline, Web of Science, CINAHL, and EBSCO databases. Keywords included "endurance training", "resistance training", "concurrent training", "muscle strength", "body composition", "sex characteristics", and "men and women". The standardized mean difference (SMD) was presented separately for men and women based on the pre- and post-intervention values for each exercise type. Results: Concurrent training showed the greatest effect on the increase in leg press muscle strength in men, and resistance training showed the greatest effect in women. Concurrent training showed the greatest effect size in both men and women in increasing bench press muscle strength. Resistance training and concurrent training showed a small effect size on lean mass reduction in both men and women. Endurance training and concurrent training significantly reduced fat mass in men. However, no significant changes in fat mass were observed in any exercise type among women. Conclusions: Concurrent training is the most efficient type of exercise for men, as it is effective in increasing upper- and lower-body muscle strength, increasing lean mass, and reducing fat mass. Resistance training is most effective in increasing muscle strength in females, whereas endurance training is most effective in reducing fat mass. However, it is difficult to corroborate these results because of the lack of study samples included in the analysis and the differences in exercise methods, participant age, and exercise duration.

The variability of anthropometric and body composition parameters in middle-aged women associated with menopause and smoking

Menopause and its related hormonal changes are associated with the variation of body composition, especially impacting adipose tissue metabolism and the reduction of lean mass. The purpose of the present study was to investigate the impact of smoking during menopause on the subsequent effects on body composition. The sample comprised of 572 Slovak women aged between 39 and 65 years (49.67±6.2). Standard anthropometric techniques were used to collect anthropometric measurements, whereas bioelectrical parameters were measured utilizing a mono-frequency bioimpedance analyzer (BIA 101). Data on menopausal status, physical activity, and smoking habits were obtained via a specific questionnaire. In postmenopausal women, our results showed a statistically significant difference between smokers and non-smokers in BMI, TBW%, ECW%, ICW%, MM%, FFM%, FM% (p &lt; 0.05). No significant differences were observed in premenopausal women, although two-way analysis of covariance revealed a significant interaction between smoking and menopausal status on the FM% (p &lt; 0.001), FFM% (p &lt; 0.001), and MM% (p = 0.002), whilst controlling for age and physical activity. In our sample group of middle-aged women, the combined impact of menopause and smoking appeared to influence anthropometric parameters and body composition.

Особенности композиционного состава тела и метаболического профиля у детей с саркопеническим ожирением

Sarcopenic obesity (SO) is characterized by a decrease of lean mass and increase of adipose tissue and is associated with various metabolic disorders in adults. The influence of the body composition on the metabolic profile in obese children remains unclear as yet. The purpose of the research was to assess body composition and metabolic profile in children with sarcopenic obesity Methods used: cross-sectional, single-center study was conducted in Feb. 2020-Jul. 2022 which included 116 children (55 boys, 61 girls) with simple obesity (SDS BMI 2.5 [2.2;2.7]) aged 7 to 17 y/o (average age 14.2 [12.3;15.5] y/o) divided into two groups depending on the presence of sarcopenic obesity. The group with sarcopenic obesity ("SO+") included 56 children (19 boys, 37 girls) with simple obesity (SDS BMI 2.5 [2.2; 2.6]). The control group ("SO-") consisted of 60 children (36 boys, 24 girls) with constitutionally exogenous obesity (SDS BMI 2.5 [2.2; 2.7]) without sarcopenia. Results: children with sarcopenic obesity were characterized by an increase in adipose tissue (39.1% [36.4; 41.9] vs 30.6% [27.6; 32.4]; p&lt;0.0001), decrease in lean mass (55.6 [44.8; 63.7] vs 45.6 [39.5; 49.7] kg; p&lt;0.0001) and skeletal muscle mass decrease (25.0 [19.2; 28.2] vs 19.4 [16.3; 22.4] kg; p&lt;0.0001) - all compared to the "SO-" group. There were no statistically significant differences in the frequency of detection of impaired glucose tolerance (p=0.672), insulin resistance (p=0.871) and non-alcoholic fatty liver disease (p=0.657) in both groups. Conclusion: sarcopenic obesity in children is characterized by a reduction of lean mass and skeletal muscle mass and is not accompanied by changes in the metabolic profile. It makes difficult to stratify metabolic risks in this group of pediatric patients.

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria.

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.

Moderators of resistance-based exercise programs' effect on sarcopenia-related measures in men with prostate cancer previously or currently undergoing androgen deprivation therapy: An individual patient data meta-analysis

IntroductionOlder men with prostate cancer are commonly affected by reductions in lean mass and physical function following androgen deprivation therapy (ADT). Resistance-based exercise programs are critical to counteract the musculoskeletal toxicities derived from prostate cancer treatment and aging. However, there is significant variability in the effects of exercise interventions. Examining demographic and clinical moderators of exercise effects in this patient group can assist in identifying which subgroups of patients benefit most. Therefore, we examined the effects and moderators of resistance-based exercise programs on sarcopenia-related outcomes that included lean mass, skeletal muscle index, physical function, and muscle strength in older men with prostate cancer. Materials and MethodsData were retrieved from the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium. For the present study, we included data from trials that examined the effects of supervised resistance-based exercise interventions on lean mass outcomes, muscle strength, and physical function in patients with prostate cancer previously or currently treated with ADT. Linear mixed models were undertaken to analyse the effects of resistance-based exercise programs considering the clustering of patients within studies. Effects were evaluated by regressing the study group on the post-intervention value of the outcome adjusted for the baseline value, while potential moderators were examined by adding the moderator and its interaction term into the regression model. ResultsA total of 560 patients with prostate cancer (age: 69.5 ± 7.8 yrs.; body mass index: 28.6 ± 4.0 kg.m−2) previously or currently treated with ADT were included. Resistance-based exercise programs resulted in significant effects on whole-body and appendicular lean mass and the skeletal muscle index (P < 0.05), with improvements observed across different characteristics. Improvements were also observed in 400-m walk and 6-m backwards tandem walk (P < 0.05), with patients presenting with lower baseline levels deriving greater exercise effects on 400-m walk (−19.4 s, 95% confidence interval [CI]: −36.6 to −2.3) and 6-m backwards tandem walk tests (−3.0 s, 95% CI: −5.7 to −0.3). For relative muscle strength, significant exercise effects were observed, with greater effects in younger patients (0.35 kg.kg−1, 95% CI: 0.22 to 0.48). DiscussionResistance-based exercise programs effectively improve well-known markers of sarcopenia in men with prostate cancer, with specific subgroups of patients, such as those younger and presenting with lower baseline levels of physical function, deriving greater effects on muscle strength and physical function, respectively.

Changes in Body Weight, Body Composition, Phase Angle, and Resting Metabolic Rate in Male Patients with Stage IV Non-Small-Cell Lung Cancer Undergoing Therapy.

Background and Objectives: Cancer treatments can adversely influence body weight status, body composition, phase angle (PhA), and resting metabolic rate (RMR), which could possibly affect disease course. Τhe aim was to assess differences in body composition, PhA, RMR, and related parameters in non-small-cell lung cancer (NSCLC) patients after treatment. Methods: The sample consisted of 82 NSCLC (stage IV) male patients (chemotherapy (C) 15.7%; immunotherapy (I) 13.3%; C + I 25.3%; (C) + radiotherapy (R) 22.9 %; and other 15.5%). Body weight and body composition, PhA, RMR, oxygen consumption (VO2), ventilation rate, and diet were assessed at baseline and at 3 months after initiation of therapy. Results: Reductions in PhA, RMR, VO2, ventilation rate, and intracellular water were observed at follow up. Weight loss was evident for 45% of patients who also had a reduction in lean body mass. In the group under C, lean mass was reduced at follow up (55.3 ± 11.53 vs. 52.4 ± 12.6, p = 0.04) without significant weight changes. In subjects with a low adherence to the Mediterranean diet (MedDietScore &lt; 30), RMR (1940 ± 485 vs. 1730 ± 338 Kcal, p = 0.001), VO2 (277.1 ± 70.2 vs. 247 ± 49.1 mL/min, p = 0.001), and ventilation rate (10.1 ± 2.28 vs. 9. ± 2 2.2 L/min, p = 0.03) were significantly reduced. The changes in body weight were positively related to % of change in fat mass (rho = 0.322, p = 0.003) and absolute lean mass change (rho = 0.534, p &lt; 0.001) and negatively associated with % of change in total body water (rho = -0.314, p = 0.004) (Spearman correlation coefficients). Conclusions: In conclusion, cancer therapy related to reductions in PhA and RMR, while lean mass reduction may be related to the type of treatment. Our results emphasize the importance of a more holistic nutritional and body composition assessment beyond body weight, to better address patients' needs in clinical practice.

Moderators of Resistance Training Effects in Overweight and Obese Adults: A Systematic Review and Meta-analysis.

This study aimed to analyze whether the effects of resistance exercise on whole-body fat and lean mass are moderated by exercise dosage (i.e., duration, volume, and intensity), age, body mass index, baseline values, assessment methods, and prescription of aerobic exercise and caloric restriction in overweight/obese adults. A systematic search was undertaken in 11 databases from inception to December 2020, with an updated search undertaken in April 2022. Eligible randomized controlled trials examined the effects of resistance-based exercise programs on whole-body fat mass and lean mass in adults who were overweight or obese. Meta-analysis was undertaken with a random-effects model. Associations between mean differences and potential moderators were tested by meta-regression models. Sixty-seven articles describing 65 trials ( n = 2537) were included. Resistance-based exercise programs resulted in a significant change of -1.6 kg (95% confidence interval [CI] = -1.9 to -1.3 kg, P < 0.001) in whole-body fat mass and +0.8 kg (95% CI = 0.6 to 0.9 kg, P < 0.001) in lean mass. Male participants experienced greater effects than females ( P < 0.001), whereas those presenting with higher levels of fat mass at baseline experienced greater reductions in this outcome ( P = 0.084). For lean mass, younger adults experienced greater improvements compared with older participants ( P = 0.009), whereas programs comprising resistance exercise and caloric restriction resulted in significant reductions in lean mass ( P = 0.035). Resistance exercise dosage or prescription of aerobic exercise was not associated with change in these outcomes. Resistance-based programs improve body composition regardless of the resistance exercise dosage or aerobic component prescribed in adults who are overweight or obese. In addition, subgroups based on demographic characteristics, baseline levels, and presence of caloric restriction may present with more favorable responses in body composition.

Changes in Body Composition, Basal Metabolic Rate, and Blood Albumin during the First Year following Laparoscopic Mini-Gastric Bypass.

Bariatric surgery is currently the only method that can significantly and continuously reduce weight and improve obesity-related comorbidities in morbidly obese patients. Significant weight loss through bariatric surgery can lead to changes in body composition. This study shows the changes in body composition, basal metabolic rate (BMR), and serum albumin in obese people following bariatric surgery. The study included 880 patients who underwent laparoscopic mini-gastric bypass surgery (LMGBP) between 2016 and 2020. The body mass index (BMI), bioelectrical impedance analysis (BIA), age, gender, blood albumin, WC (waist circumference), HC (hip circumference), BMR, and blood albumin were recorded at 0, 3, 6, and 12 months, postoperatively. The reduction in serum albumin concentration was not consistent with weight loss. Bariatric surgery promotes the breakdown of both fat and lean mass on the arms, torso, and thighs. This size reduction usually aggravates the concomitant skin redundancy in these areas which is a challenge for the plastic surgery team. Interestingly, the rate of lean mass reduction of the arms is faster than that of the torso and thighs. Excessive loss of lean body mass will also lower BMR and lead to subsequent weight gain. Despite the faster loss of proteins and lean mass in somatic areas, internal organs and viscera lose fats faster than proteins. According to this study, visceral proteins are the latest proteins to be affected by weight loss. This finding shows a different metabolic response of viscera comparing to somatic areas.

Rev1 deficiency induces replication stress to cause metabolic dysfunction differently in males and females.

DNA damage responses compete for cellular resources with metabolic pathways, but little is known about the metabolic consequences of impaired DNA replication, a process called replication stress. Here we characterized the metabolic consequences of DNA replication stress at endogenous DNA lesions by using mice with a disruption of Rev1, a translesion DNA polymerase specialized in the mutagenic replication of damaged DNA. Male and female Rev1 knockout (KO) mice were compared with wild-type (WT) mice and followed over time to study the natural course of body weight gain and glucose tolerance. Follow-up measurements were performed in female mice for in-depth metabolic characterization. Body weight and fat mass were only increased in female KO mice versus WT mice, whereas glucose intolerance and a reduction in lean mass were observed in both sexes. Female KO mice showed reduced locomotor activity while male KO mice showed increased activity as compared with their WT littermates. Further characterization of female mice revealed that lipid handling was unaffected by Rev1 deletion. An increased respiratory exchange ratio, combined with elevated plasma lactate levels and increased hepatic gluconeogenesis indicated problems with aerobic oxidation and increased reliance on anaerobic glycolysis. Supplementation with the NAD+ precursor nicotinamide riboside to stimulate aerobic respiration failed to restore the metabolic phenotype. In conclusion, replication stress at endogenous DNA lesions induces a complex metabolic phenotype, most likely initiated by muscular metabolic dysfunction and increased dependence on anaerobic glycolysis. Nicotinamide riboside supplementation after the onset of the metabolic impairment did not rescue this phenotype.NEW & NOTEWORTHY An increasing number of DNA lesions interferes with cellular replication leading to metabolic inflexibility. We utilized Rev1 knockout mice as a model for replication stress, and show a sex-dependent metabolic phenotype, with a pronounced reduction of lean mass and glucose tolerance. These data indicate that in obesity, we may end up in an infinite loop where metabolic disturbance promotes the formation of DNA lesions, which in turn interferes with cellular replication causing further metabolic disturbances.

Effect of a Remotely Delivered Weight Loss Intervention in Early-Stage Breast Cancer: Randomized Controlled Trial.

Limited evidence exists on the effects of weight loss on chronic disease risk and patient-reported outcomes in breast cancer survivors. Breast cancer survivors (stage I–III; body mass index 25–45 kg/m2) were randomized to a 12-month, remotely delivered (22 telephone calls, mailed material, optional text messages) weight loss (diet and physical activity) intervention (n = 79) or usual care (n = 80). Weight loss (primary outcome), body composition, metabolic syndrome risk score and components, quality of life, fatigue, musculoskeletal pain, menopausal symptoms, fear of recurrence, and body image were assessed at baseline, 6 months, 12 months (primary endpoint), and 18 months. Participants were 55 ± 9 years and 10.7 ± 5.0 months post-diagnosis; retention was 81.8% (12 months) and 80.5% (18 months). At 12-months, intervention participants had significantly greater improvements in weight (−4.5% [95%CI: −6.5, −2.5]; p < 0.001), fat mass (−3.3 kg [−4.8, −1.9]; p < 0.001), metabolic syndrome risk score (−0.19 [−0.32, −0.05]; p = 0.006), waist circumference (−3.2 cm [−5.5, −0.9]; p = 0.007), fasting plasma glucose (−0.23 mmol/L [−0.44, −0.02]; p = 0.032), physical quality of life (2.7 [0.7, 4.6]; p = 0.007; Cohen’s effect size (d) = 0.40), musculoskeletal pain (−0.5 [−0.8, −0.2]; p = 0.003; d = 0.49), and body image (−0.2 [−0.4, −0.0]; p = 0.030; d = 0.31) than usual care. At 18 months, effects on weight, adiposity, and metabolic syndrome risk scores were sustained; however, significant reductions in lean mass were observed (−1.1 kg [−1.7, −0.4]; p < 0.001). This intervention led to sustained improvements in adiposity and metabolic syndrome risk.

Energy expenditure, body composition and dietary habits in progressive supranuclear palsy.

IntroductionLittle is known about metabolic changes in progressive supranuclear palsy. Goals of the present study are to: (1) investigate whether early progressive supranuclear palsy is associated with changes in energy expenditure, body composition and dietary intake compared with Parkinson’s disease and healthy controls; (2) assess the accuracy of the Harris–Benedict equation to predict measured rest energy expenditure in progressive supranuclear palsy; (3) verify differences according to sex, phenotypes, disease severity and presence of dysphagia in progressive supranuclear palsy.MethodsTwenty-one progressive supranuclear palsy, 41 Parkinson’s disease and nine healthy controls were included. Rest energy expenditure was assessed with indirect calorimeter, body composition with bio-impedance analysis and physical activity and dietary intake were estimated with a validated frequency questionnaire. Parametric testing was used to analyze differences between groups.ResultsProgressive supranuclear palsy showed reduced total daily energy expenditure and physical activity compared to both other cohorts (p < 0.001) and a tendency toward lower fat-free mass compared to Parkinson’s disease (p > 0.05). Limited accuracy was shown for the Harris–Benedict equation (accurate prediction frequency < 60%). Greater disease severity was associated with lower rest energy expenditure (p = 0.030), fat-free mass (p = 0.026) and muscle mass (p = 0.029).ConclusionGreater disease severity is associated with reduction in rest energy expenditure likely due to the reduction in lean mass and muscle mass. Such data may pave the way to clinical trials evaluating the efficacy of muscle-targeted nutritional support and physical therapy in preserving muscle mass and improving motor performances in progressive supranuclear palsy at early stages.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-021-10846-6.

A protein-supplemented very-low-calorie diet does not mitigate reductions in lean mass and resting metabolic rate in subjects with overweight or obesity: A randomized controlled trial

The European Food Safety Authority recently recommended an increase in the protein content of total diet replacement (TDR) products from 50 to 75g/day. The rationale was to minimize reductions in lean mass (LM) and resting metabolic rate (RMR) that occur with weight loss, and thereby facilitate maintenance of lost weight. We sought to directly compare the efficacy of TDR regimens with the new vs the current protein requirement. We randomized 108 adults with overweight or obesity (body mass index 28-40kg/m2) to very-low-calorie diets (VLCD) with either 52 or 77g/day protein for 8 weeks (total energy intake of 600 or 700kcal/day, respectively). LM was determined by dual energy X-ray absorptiometry and RMR by indirect calorimetry. Attrition rate was 22% in both groups. Both VLCDs decreased body weight, fat mass, LM, and RMR (all P<0.05). Significant time-by-group interactions were detected for weight and fat mass (both P<0.05), with corresponding reductions being smaller in the higher-protein than the standard-protein VLCD, likely because of the added calories. On the other hand, reductions in LM (6% from baseline) and RMR (9-10% from baseline) did not differ between groups (P=0.155 and P=0.389, respectively), and the contribution of LM to total weight loss was identical (27±2% of lost weight, P=0.973). Our results indicate that the proposed increase in the protein content of TDR products does not attenuate reductions in LM and RMR in individuals with overweight and obesity who are treated with <800kcal/day VLCDs for 2 months. ClinicalTrials.gov # NCT04156165.

Role of growth hormone in hepatic and intestinal triglyceride-rich lipoprotein metabolism

Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism. We aimed to examine the direct and/or indirect role of GH on TRL metabolism. We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults. After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III. In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism.

Pegbelfermin, a PEGylated FGF21 analogue, has pharmacology without bone toxicity after 1-year dosing in skeletally-mature monkeys

Pegbelfermin (PGBF) is a PEGylated fibroblast growth factor 21 (FGF21) analogue in development for treatment of nonalcoholic steatohepatitis (NASH). Mouse models highlight potential utility of FGF21 in NASH, but also suggest negative effects on bone, though these findings are confounded by profound FGF21-related decreases in body mass/growth. This study aimed to profile PGBF-related bone effects in adult nonhuman primates after long-term, clinically-relevant exposures. Adult male cynomolgus monkeys received weekly subcutaneous PGBF (0.3, 0.75 mg/kg) or control injections for 1 year (n = 5/group). Assessments included body weight, clinical chemistry, adiponectin levels, bone turnover biomarkers, skeletal radiography, pharmacokinetics, immunogenicity, and histopathology. Bone densitometry and body composition were evaluated in vivo and/or ex vivo with dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and biomechanical strength testing. After 1 year of PGBF administration, there was clear evidence of sustained PGBF pharmacology in monkeys (peak increase in serum adiponectin of 1.7× and 2.35× pretest at 0.3 and 0.75 mg/kg PGBF, respectively) and decreased body weight compared with control at exposures comparable to those tested in humans. At 0.75 mg/kg PGBF, pharmacologically-mediated reductions in lean mass, lean area, and fat area were observed relative to controls. There were no PGBF-related effects on bone biomarkers, radiography, densitometry, or strength. Together, these data demonstrate that PGBF did not adversely alter bone metabolism, density, or strength following 1 year of dosing at clinically relevant (0.7–2.2× human AUC[0-168 h] at 20 mg once weekly), pharmacologically-active exposures in adult monkeys, suggesting a low potential for negative effects on bone quality in adult humans.

Circulating Levels of Sclerostin Predict Glycemic Improvement after Sleeve Gastrectomy.

Among the different effects of bariatric surgery, here we focus on bone-derived inflammatory molecules, and in particular, sclerostin; an osteocyte product potentially associated with cardio-metabolic diseases. In 94 morbidly obese patients undergoing laparoscopic sleeve gastrectomy (SG), over-time changes in anthropometric and biochemical measures—including insulin resistance (IR) indexes—were correlated with serum sclerostin levels. Sclerostin was positively associated with anthropometric indexes of obesity, and inversely with IR, namely homeostatic model assessment for peripheral insulin sensitivity (HOMA2%S) (r = −0.218; p = 0.045). Sclerostin emerged as the only significant predictor of HOMA2-%S normalization, independently of demographic and anthropometric variables (OR 1.01 (95% CI 1.00–1.02); p = 0.024). We also identified two distinct patterns of serum sclerostin change: the higher/lower sclerostin levels at baseline, the greater their post-surgical reduction/increase (p < 0.001 for all subgroups). Among those two patterns, especially the post-surgery increase in serum sclerostin was associated with lean mass reduction, without any association with IR indexes. Although counterintuitive, this change was likely dependent on the post-surgical increase in bone turnover. In conclusion, baseline serum levels of sclerostin correlate with anthropometric measures of obesity and IR, and the ability to predict glycemic improvements after SG. Specifically, serum sclerostin was closely associated with peripheral insulin sensitivity (HOMA2-%S), thus supporting the role of skeletal muscle/bone interactions in metabolic diseases.

Obesity Augments Glucocorticoid-Dependent Muscle Atrophy in Male C57BL/6J Mice.

Glucocorticoids promote muscle atrophy by inducing a class of proteins called atrogenes, resulting in reductions in muscle size and strength. In this work, we evaluated whether a mouse model with pre-existing diet-induced obesity had altered glucocorticoid responsiveness. We observed that all animals treated with the synthetic glucocorticoid dexamethasone had reduced strength, but that obesity exacerbated this effect. These changes were concordant with more pronounced reductions in muscle size, particularly in Type II muscle fibers, and potentiated induction of atrogene expression in the obese mice relative to lean mice. Furthermore, we show that the reductions in lean mass do not fully account for the dexamethasone-induced insulin resistance observed in these mice. Together, these data suggest that obesity potentiates glucocorticoid-induced muscle atrophy.

Anthropometrics by Three-Dimensional Photonic Scanner in Patients with Obesity Before and After Bariatric Surgery.

We studied body composition by three-dimensional photonic scanning (3DPS) and metabolic biomarkers in a large ethnically diverse cohort of individuals with severe obesity before and after weight loss by Roux-en-Y gastric bypass (RYGB) or adjustable gastric banding (AGB) surgery. Male and female participants (n = 95) underwent 3DPS testing in the weeks preceding bariatric surgery (baseline), and 1year after either RYGB (n = 34) or AGB (n = 9). Principal component analysis showed that A1C and HDL cholesterol clustered with waist-to-hip ratio (WHR). Both RYGB and AGB surgeries led to similar improvements in A1C and lipids after 1year. RYGB led to greater decreases in body weight, and in most anthropometric measures, compared with AGB at 1year. However, after accounting for weight loss differences, RYGB and AGB groups did not differ in regional decreases in circumferences or volumes; the exception was a greater reduction in lean mass in RYGB compared with AGB. Distribution of weight loss, assessed by 3DPS, did not differ between RYGB and AGB, but surgery type predicted change in lean mass at 1year.

The Interplay Between Bone and Glucose Metabolism.

The multiple endocrine functions of bone other than those related to mineral metabolism, such as regulation of insulin sensitivity, glucose homeostasis, and energy metabolism, have recently been discovered. In vitro and murine studies investigated the impact of several molecules derived from osteoblasts and osteocytes on glucose metabolism. In addition, the effect of glucose on bone cells suggested a mutual cross-talk between bone and glucose homeostasis. In humans, these mechanisms are the pivotal determinant of the skeletal fragility associated with both type 1 and type 2 diabetes. Metabolic abnormalities associated with diabetes, such as increase in adipose tissue, reduction of lean mass, effects of hyperglycemia per se, production of the advanced glycation end products, diabetes-associated chronic kidney disease, and perturbation of the calcium-PTH-vitamin D metabolism, are the main mechanisms involved. Finally, there have been multiple reports of antidiabetic drugs affecting the skeleton, with differences among basic and clinical research data, as well as of anti-osteoporosis medication influencing glucose metabolism. This review focuses on the aspects linking glucose and bone metabolism by offering insight into the most recent evidence in humans.

Resveratrol and metabolic health in COPD: A proof-of-concept randomized controlled trial.

Patients with COPD are often characterized by disturbed metabolic health which is reflected in altered body composition. Current studies in healthy subjects suggest that resveratrol improves metabolic health by enhancing muscle mitochondrial function and adipose tissue morphology. The primary objective was to investigate the effect of four weeks resveratrol supplementation on muscle mitochondrial function in patients with COPD. Secondary objectives were to investigate the effect of resveratrol on adipose tissue inflammatory and metabolic gene expression, systemic inflammation and body composition in patients with COPD. In a double-blind randomized placebo-controlled proof-of-concept study, 21 COPD patients (FEV1: 53±15% predicted; age: 67±9 years and BMI: 24.5±3.3kg/m2) received resveratrol (150mg/day) or placebo for four weeks. Before and after intervention, blood samples, quadriceps muscle and subcutaneous abdominal fat biopsies were obtained for metabolic and inflammatory profiling. Body composition was assessed by dual energy X-ray absorptiometry. Muscle mitochondrial biogenesis regulators AMPK, SIRT1 and PGC-1α as well as mitochondrial respiration, Oxphos complexes, oxidative enzyme activities and kynurenine aminotransferases were not improved by resveratrol. Plasma high-sensitive C-reactive protein and kynurenine did not change after resveratrol supplementation. Adipose tissue inflammatory markers were unaffected by resveratrol, while markers of glycolysis and lipolysis were significantly increased compared to placebo supplementation. Body weight decreased after resveratrol supplementation (resveratrol-0.95±1.01kg vs placebo-0.16±0.66kg, p=0.049) due to a reduction in lean mass (resveratrol-1.79±1.67kg vs 0.37±0.86kg, p=0.026). We do not confirm previously reported positive effects of resveratrol on skeletal muscle mitochondrial function in patients with COPD, but show an unexpected decline in lean mass. Clinicaltrials.gov NCT02245932.