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Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49) and women (n = 52) with and without NAFLD. Hepatic fat content was measured using proton magnetic resonance spectroscopy (1H MRS). Serum samples were analyzed using a nuclear magnetic resonance (NMR) metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR. Muscle protein expression was analyzed by Western blot. Increased branched-chain amino acid (BCAA), aromatic amino acid (AAA) and orosomucoid were associated with liver fat accumulation already in its early stage, independent of sex, obesity or insulin resistance (p<0.05 for all). Significant down-regulation of BCAA catabolism and fatty acid and energy metabolism was observed in the adipose tissue of the NAFLD group (p<0.001for all), whereas no aberrant gene expression in the skeletal muscle was found. Reduced BCAA catabolic activity was inversely associated with serum BCAA and liver fat content (p<0.05 for all). Liver fat accumulation, already in its early stage, is associated with increased serum branched-chain and aromatic amino acids. The observed associations of decreased BCAA catabolism activity, mitochondrial energy metabolism and serum BCAA concentration with liver fat content suggest that adipose tissue dysfunction may have a key role in the systemic nature of NAFLD pathogenesis.

Executive functions underlie self-regulation and are thus important for physical activity and adaptation to new situations. The aim was to investigate, if yearlong physical and cognitive training (PTCT) had greater effects on physical activity among older adults than physical training (PT) alone, and if executive functions predicted physical activity at baseline, after six (6m) and twelve months (12m) of the interventions, one-year post-intervention follow-up and an extended follow-up during COVID-19 lockdown. Data from a single-blinded, parallel-group randomized controlled trial (PASSWORD-study, ISRCTN52388040) were utilized. Participants were 70-85 years old community-dwelling men and women from Jyväskylä, Finland. PT (n = 159) included supervised resistance, walking and balance training, home-exercises and self-administered moderate activity. PTCT (n = 155) included PT and cognitive training targeting executive functions on a computer program. Physical activity was assessed with a one-item, seven-scale question. Executive functions were assessed with color-word Stroop, Trail Making Test (TMT) B-A and Letter Fluency. Changes in physical activity were modeled with multinomial logistic models and the impact of executive functions on physical activity with latent change score models. No significant group-by-time interaction was observed for physical activity (p>0.1). The subjects were likely to select an activity category higher than baseline throughout the study (pooled data: B = 0.720-1.614, p<0.001-0.046). Higher baseline Stroop predicted higher physical activity through all subsequent time-points (pooled data: B = 0.011-0.013, p = 0.015-0.030). Higher baseline TMT B-A predicted higher physical activity at 6m (pooled data: B = 0.007, p = 0.006) and during COVID-19 (B = 0.005, p = 0.030). In the PT group, higher baseline Letter Fluency predicted higher physical activity at 12m (B = -0.028, p = 0.030) and follow-up (B = -0.042, p = 0.002). Cognitive training did not have additive effects over physical training alone on physical activity, but multicomponent training and higher executive function at baseline may support adaptation to and maintenance of a physically active lifestyle among older adults.

Background Low physical activity is a major risk for sarcopenia. Whether training according to physical activity guidelines accompanied with cognitive training is effective on sarcopenia, remains unclear. Aims We investigated whether the effects of 12-month physical and cognitive training (PTCT) and physical training (PT) on grip and knee extension strength, muscle mass, and walking speed differed between older adults with and without sarcopenia. Methods Community-dwelling older adults ( N  = 314, mean age 74.5 ± 3.8 years, 60% women) who did not meet physical activity guidelines were randomized to PTCT and PT groups. PT for both groups included supervised and home-based multicomponent physical training. Cognitive training (CT) included computer-based exercises for executive functioning. Sarcopenia was determined according to the European Working Group on Sarcopenia in Older People 2019 criteria. Generalized estimation equation analysis were conducted. Results Compared to PT, PTCT had no additive effect on strength, muscle mass, or walking speed in participants with or without sarcopenia. In pooled data (PT + PTCT) change in the grip strength was greater in sarcopenia ( n  = 49) group compared to non-sarcopenia ( n  = 264) group (interaction, p  =.014). Both groups improved knee extension strength, and walking speed, but no statistically significant difference between the groups were observed. Muscle mass did not change in either group. Conclusion Physical training according to physical activity recommendations improves muscle strength, walking speed, and maintains muscle mass in sarcopenia. Additional cognitive training had no benefits on these outcomes. Trial registration number ISRCTN52388040 and date of registration 20/1/2017.

Summary MiRNAs are fine‐tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co‐twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen‐based hormone replacement therapy (HRT) to explore estrogen‐dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62‐years‐old monozygotic female twin pairs discordant for HRT (median 7 years). MCF‐7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR‐182, miR‐223 and miR‐142‐3p expressions in HRT using than in their nonusing co‐twins. Insulin/IGF‐1 signaling emerged one common pathway targeted by these miRNAs. IGF‐1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR‐182 and miR‐223 on IGF‐1R and FOXO3A mRNA as well as a dose‐dependent miR‐182 and miR‐223 down‐regulations concomitantly with up‐regulation of FOXO3A and IGF‐1R expression. Novel finding is the postmenopausal HRT‐reduced miRs‐182, miR‐223 and miR‐142‐3p expression in female skeletal muscle. The observed miRNA‐mediated enhancement of the target genes' IGF‐1R and FOXO3A expression as well as the activation of insulin/IGF‐1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.

Exosomes participate in intercellular messaging by transporting bioactive lipid-, protein- and RNA-molecules and -complexes. The contents of the exosomes reflect the physiological status of an individual making exosomes promising targets for biomarker analyses. In the present study we extracted exosome microRNAs (exomiRs) from serum samples of premenopausal women (n = 8) and monozygotic postmenopausal twins (n = 10 female pairs), discordant for the use of estrogenic hormone replacement therapy (HRT), in order to see whether the age or/and the use of HRT associates with exomiR content. A total of 241 exomiRs were detected by next generation sequencing, 10 showing age, 14 HRT and 10 age +HRT -related differences. When comparing the groups, differentially expressed miRs were predicted to affect cell proliferation processes showing inactivation with younger age and HRT usage. MiR-106-5p, -148a-3p, -27-3p, -126-5p, -28-3p and -30a-5p were significantly associated with serum 17β-estradiol. MiRs formed two hierarchical clusters being indicative of positive or negative health outcomes involving associations with body composition, serum 17β-estradiol, fat-, glucose- and inflammatory markers. Circulating exomiR clusters, obtained by NGS, could be used as indicators of metabolic and inflammatory status affected by hormonal changes at menopause. Furthermore, the individual effects of HRT-usage could be evaluated based on the serum exomiR signature.

Background Safe and stable walking is a complex process involving the interaction of neuromuscular, sensory and cognitive functions. As physical and cognitive functions deteriorate with ageing, training of both functions may have more beneficial effects on walking and falls prevention than either alone. This article describes the study design, recruitment strategies and interventions of the PASSWORD study investigating whether a combination of physical and cognitive training (PTCT) has greater effects on walking speed, dual-task cost in walking speed, fall incidence and executive functions compared to physical training (PT) alone among 70–85-year-old community-dwelling sedentary or at most moderately physically active men and women. Methods Community-dwelling sedentary or at most moderately physically active, men and women living in the city of Jyväskylä will be recruited and randomized into physical training (PT) and physical and cognitive training (PTCT). The 12-month interventions include supervised training sessions and home exercises. Both groups attend physical training intervention, which follows the current physical activity guidelines. The PTCT group performes also a web-based computer program targeting executive functions. Outcomes will be assessed at baseline and at 6 and 12 months thereafter. Falls data are collected during the interventions and the subsequent one-year follow-up. The primary outcome is 10-m walking speed. Secondary outcomes include 6-min walking distance, dual-task cost in walking speed, fall incidence and executive function assessed with color Stroop and Trail Making A and B tests. Explanatory outcomes include e.g. body composition and bone characteristics, physical performance, physical activity, life-space mobility, fall-related self-efficacy, emotional well-being and personality characteristics. Discussion The study is designed to capture the additive and possible synergistic effects of physical and cognitive training. When completed, the study will provide new knowledge on the effects of physical and cognitive training on the prevention of walking limitations and rate of falls in older people. The expected results will be of value in informing strategies designed to promote safe walking among older people and may have a significant health and socio-economic impact. Trial registration ISRCTN52388040 .

Serotonin plays a potential role in bone metabolism, but the nature and extent of this relationship is unclear and human studies directly addressing the skeletal effect of circulating serotonin are rare. The study aimed to investigate the associations between serum serotonin and bone traits at multiple skeletal sites in women and men. Subjects were part of the CALEX-family study and comprised 235 young women, 121 premenopausal women, 124 postmenopausal women, and 168 men. Body composition was assessed using DXA, as was areal bone mineral density (aBMD) of spine, femur and whole body. In addition, pQCT was used to determine bone properties at tibial midshaft and distal radius. Fasting serum serotonin concentration was assessed using a competitive enzyme-linked immunosorbent assay. Serum serotonin declined with advancing age both in females and males (all p<0.01). Serotonin was negatively correlated with weight, BMI, lean and fat mass in women (r = -0.22 to -0.39, all p<0.001), but positively with height and lean mass in men (all p<0.01). In the premenopausal women, serotonin was negatively correlated with lumbar spine aBMD (r = -0.23, p<0.05) but the statistical significance disappeared after adjustment for weight. Conversely, in postmenopausal women, serotonin was positively correlated with whole body and femur aBMD, as well as with distal radius bone mineral content and volumetric BMD (r = 0.20 to 0.30, all p<0.05), and these associations remained significant after adjustment for weight. In men, no significant associations were found between serotonin and bone traits. Serum serotonin is positively associated with bone traits in postmenopausal women, but not in premenopausal women or men. This partially supports the idea of circulating serotonin playing a role in the regulation of bone metabolism, but also indicates the importance of gender and age specific factors.

Background Personality reflects relatively stable and pervasive tendencies in feeling, thinking and behaving. While previous studies have found higher extraversion and lower neuroticism to be linked to higher self-reported physical activity levels, larger studies using accelerometer-measured physical activity are lacking. This study investigated the cross-sectional associations of extraversion and neuroticism with both accelerometer-measured and self-reported physical activity and the role of these personality traits in possible discrepancies between these two measures of physical activity among Finnish adults. Methods Two community-dwelling samples were used in this study: a) 47–55-yr-old women ( n  = 1098) and b) 70–85-yr-old women and men ( n  = 314). In both samples, extraversion and neuroticism were assessed by the 19-item short form of the Eysenck Personality Inventory. Physical activity was assessed with hip-worn tri-axial accelerometers and self-reported questions. Regression analyses were adjusted by age, BMI and education. Results In the middle-aged women, neuroticism was negatively associated with accelerometer-measured leisure time moderate-to-vigorous physical activity (β = −.07, p  = .036) and with self-reported physical activity (β = −.08, p  = .021), while extraversion was positively associated with self-reported physical activity (β = .10, p  = .005). No associations of extraversion or neuroticism with physical activity were found in the older men and women. Older adults who scored high in neuroticism reported less physical activity than what was measured by accelerometers (β = −.12, p  = .039). Extraversion was not associated with discrepancy between self-reported and accelerometer-measured leisure time physical activity in either sample. Conclusions Neuroticism was associated with lower leisure-time physical activity levels and extraversion with higher self-reported physical activity among middle-aged women. Neuroticism and extraversion were unrelated to physical activity among older adults, but older adults with high neuroticism seemed to underreport their physical activity level. The role of personality in the discrepancy between self-reported and device-based physical activity warrants further research.

Hormonal and neuromuscular adaptations to strength training were studied in eight male strength athletes (SA) and eight non-strength athletes (NA). The experimental design comprised a 21-week strength-training period. Basal hormonal concentrations of serum total testosterone (T), free testosterone (FT) and cortisol (C) and maximal isometric strength, right leg 1 repetition maximum (RM) of the leg extensors were measured at weeks 0, 7, 14 and 21. Muscle cross-sectional area (CSA) of the quadriceps femoris was measured by magnetic resonance imaging (MRI) at weeks 0 and 21. In addition, the acute heavy resistance exercises (AHRE) (bilateral leg extension, five sets of ten RM, with a 2-min rest between sets) including blood samples for the determination of serum T, FT, C, and GH concentrations were assessed before and after the 21-week training. Significant increases of 20.9% in maximal force and of 5.6% in muscle CSA in NA during the 21-week strength training period were greater than those of 3.9% and -1.8% in SA, respectively. There were no significant changes in serum basal hormone concentrations during the 21-week experiment. AHRE led to significant acute decreases in isometric force and acute increases in serum hormones both at weeks 0 and 21. Basal T concentrations (mean of 0, 7, 14 and 21 weeks) and changes in isometric force after the 21-week period correlated with each other (r=0.84, P<0.01) in SA. The individual changes in the acute T responses between weeks 0 and 21 and the changes in muscle CSA during the 21-week training correlated with each other (r=0.76, P<0.05) in NA. The correlations between T and the changes in isometric strength and in muscle CSA suggest that both serum basal testosterone concentrations and training-induced changes in acute testosterone responses may be important factors for strength development and muscle hypertrophy.

Background Physical inactivity is an important factor in the development of sarcopenia. This cross-sectional study explores the prevalence of sarcopenia and associations of physical activity (PA) with sarcopenia in two exercise trial populations. These study groups are clinically meaningful community-dwelling populations at increased risk for sarcopenia: older adults not meeting the PA guidelines and those with a recent hip fracture (HF). Methods Data from 313 older adults who did not meet the PA guidelines (60% women; age 74.5 ± 3.8, body mass index 27.9 ± 4.7) and 77 individuals with HF diagnosed on average 70 ± 28 days earlier (75% women; age 79.3 ± 7.1, body mass index 25.3 ± 3.6) were included in this study. Grip strength and muscle mass (Dual-energy X-ray absorptiometry [DXA] in older adults not meeting the PA guidelines and bioimpedance analysis in participants with HF) were used to assess sarcopenia according to the European Working Group in Older People 2019 (EWGSOP2) criteria. The current level of PA was self-reported using a question with seven response options in both study groups and was measured with a hip-worn accelerometer for seven consecutive days in older adults not meeting the PA guidelines. Results The prevalence of sarcopenia and probable sarcopenia was 3% ( n  = 8) and 13% ( n  = 41) in the older adults not meeting the PA guidelines and 3% ( n  = 2) and 40% ( n  = 31) in the HF group, respectively. In the age- and sex-adjusted logistic regression model, the lowest levels of self-reported PA were associated with increased probable sarcopenia and sarcopenia risk in older adults not meeting the PA guidelines (OR 2.8, 95% CI, 1.3–6.1, p  = 0.009) and in the HF group (OR 3.9, 95% CI, 1.4–11.3, p  = 0.012). No significant associations between accelerometer-measured PA and probable sarcopenia or sarcopenia were found. Conclusions Probable sarcopenia is common among community-dwelling older adults not meeting the PA guidelines and very common among individuals recovering from HF who are able to be involved in exercise interventions. In addition, since low PA is associated with higher probable sarcopenia and sarcopenia risk, it is recommended to screen for sarcopenia and promote regular physical activity to prevent sarcopenia in these populations.