Altered muscle mitochondrial, inflammatory and trophic markers, and reduced exercise training adaptations in type 1 diabetes

none7sìGrowing evidence of impaired skeletal muscle health in peoplewith type 1 diabetes points toward the presence of a mild myopathy in this population. However, this myopathic condition is not yet well characterised and often overlooked, even though it might affect the whole-body glucose homeostasis and the development of comorbidities. This study aimed to compare skeletal muscle adaptations and changes in glycaemic control after 12 weeks of combined resistance and aerobic (COMB) training between people with type 1 diabetes and healthy controls, and to determine whether the impaired muscle health in type 1 diabetes can affect the exercise-induced adaptations. The COMB training intervention increased aerobic capacity and muscle strength in both healthy and type 1 diabetes sedentary participants, although these improvements were higher in the control group. Better glucose control, reduced glycaemic fluctuations and fewer hypoglycaemic events were recorded at post- compared to pre-intervention in type 1 diabetes. Analysis of muscle biopsies showed an alteration of muscle markers of mitochondrial functions, inflammation, ageing and growth/atrophy compared to the control group. These muscular molecular differences were only partially modified by the COMB training and might explain the reduced exercise adaptation observed in type 1 diabetes. In brief, type 1 diabetes impairs many aspects of skeletal muscle health and might affect the exercise-induced adaptations. Defining the magnitude of diabetic myopathy and the effect of exercise, including longer duration of the intervention, will drive the development of strategies to maximise muscle health in the type 1 diabetes population.openMinnock, Dean; Annibalini, Giosuè; Valli, Giacomo; Saltarelli, Roberta; Krause, Mauricio; Barbieri, Elena; De Vito, GiuseppeMinnock, Dean; Annibalini, Giosuè; Valli, Giacomo; Saltarelli, Roberta; Krause, Mauricio; Barbieri, Elena; De Vito, Giusepp

Effects of acute aerobic, resistance and combined exercises on 24-h glucose variability and skeletal muscle signalling responses in type 1 diabetics

Purpose: To compare the effect of high-intensity aerobic (AER), resistance (RES), and combined (COMB: RES + AER) exercise, on interstitial glucose (IG) variability and skeletal muscle signalling pathways in type 1 diabetes (T1D). Methods: T1D participants (6 M/6F) wore a flash glucose monitoring system in four randomized sessions: one control (CONT), and one AER, RES and COMB (40 min each). Mean amplitude of glycemic excursions (MAGE), standard deviation (SD) and coefficient variation (CV) of IG were used to compare the 24 h post-exercise IG variability. Blood and muscle samples were collected to compare exercise-induced systemic and muscle signalling responses related to metabolic, growth and inflammatory adaptations. Results: Both RES and COMB decreased the 24 h MAGE compared to CONT; additionally, COMB decreased the 24 h SD and CV. In the 6-12 h post-exercise, all exercise modalities reduced the IG CV while SD decreased only after COMB. Both AER and COMB stimulated the PGC-1α mRNA expression and promoted the splicing of IGF-1Ea variant, while Akt and p38MAPK phosphorylation increased only after RES and COMB. Additionally, COMB enhanced eEF2 activation and RES increased myogenin and MRF4 mRNA expression. Blood lactate and glycerol levels and muscle IL-6, TNF-α, and MCP-1 mRNAs increased after all exercise sessions, while serum CK and LDH level did not change. Conclusion: COMB is more effective in reducing IG fluctuations compared to single-mode AER or RES exercise. Moreover, COMB simultaneously activates muscle signalling pathways involved in substrate metabolism and anabolic adaptations, which can help to improve glycaemic control and maintain muscle health in T1D

Treatment of Achilles Tendinopathy in Recreational Runners with Peritendinous Hyaluronic Acid Injections: A Viscoelastometric, Functional, and Biochemical Pilot Study

Background: Achilles tendinopathy (AT) affects ca. 10 million recreational runners in Europe; the practice of hyaluronic acid (HA) infiltration is being increasingly adopted. The aim of this pilot study was to monitor the effects of a three-local time-spaced injections regimen of HA in the treatment of AT in middle-aged runners combining for the first time viscoelastometric, biochemical, and functional methodologies with routine clinical examinations. Methods: Eight male runners (Age 49.3 ± 3.9), diagnosed for unilateral AT, were given three ultrasound (US) guided peritendinous HA injections at the baseline (T0) and every fifteenth day with a follow-up on the forty-fifth day (T1, T2, and T3). At all-time points patients were assessed for viscoelastic tone and stiffness, maximal voluntary isometric contraction (MVIC), and pain level (Likert scale 0-5). The peritendinous effusions of the injured tendon were collected at T0 and T2 to quantify the volume variations and the IL-1β and MMP-3 levels. Results: At T0 MVIC and pain score were significantly lower and higher, respectively, in injured tendons. The volume, IL-1β and MMP-3 levels decreased in the course of treatment and the clinical endpoints ameliorated over time. Tone, stiffness, and functional performance also varied significantly at T2 and T3, as compared to T0. Conclusions: The sequential peritendinous injections of HA were effective in the amelioration of the clinical symptoms, as well as of the functional and viscoelastic state associated with AT. The determination of the viscoelastometric state may help to precisely evaluate the healing process in AT patients

Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation

none14sìThe insulin-like growth factor-1 (IGF-1) signaling pathway is crucial for the regulation of growth and development. The correct processing of the IGF-1Ea prohormone (proIGF-1Ea) and the IGF-1 receptor (IGF-1R) peptide precursor requires proper N-glycosylation. Deficiencies of N-linked glycosylation lead to a clinically heterogeneous group of inherited diseases called Congenital Disorders of Glycosylation (CDG). The impact of N-glycosylation defects on IGF-1/IGF-1R signaling components is largely unknown. In this study, using dermal fibroblasts from patients with different CDG [PMM2-CDG (n = 7); ALG3-CDG (n = 2); ALG8-CDG (n = 1); GMPPB-CDG (n = 1)], we analyzed the glycosylation pattern of the proIGF-1Ea, IGF-1 secretion efficiency and IGF-1R signaling activity. ALG3-CDG, ALG8-CDG, GMPPB-CDG and some PMM2-CDG fibroblasts showed hypoglycosylation of the proIGF-1Ea and lower IGF-1 secretion when compared with control (CTR). Lower IGF-1 serum concentration was observed in ALG3-CDG, ALG8-CDG and in some patients with PMM2-CDG, supporting our in vitro data. Furthermore, reduced IGF-1R expression level was observed in ALG3-CDG, ALG8-CDG and in some PMM2-CDG fibroblasts. IGF-1-induced IGF-1R activation was lower in most PMM2-CDG fibroblasts and was associated with decreased ERK1/2 phosphorylation as compared to CTR. In general, CDG fibroblasts showed a slight upregulation of Endoplasmic Reticulum (ER) stress genes compared with CTR, uncovering mild ER stress in CDG cells. ER-stress-related gene expression negatively correlated with fibroblasts IGF-1 secretion. This study provides new evidence of a direct link between N-glycosylation defects found in CDG and the impairment of IGF-1/IGF-1R signaling components. Further studies are warranted to determine the clinical consequences of reduced systemic IGF-1 availability and local activity in patients with CDG.openDi Patria, Laura; Annibalini, Giosuè; Morrone, Amelia; Ferri, Lorenzo; Saltarelli, Roberta; Galluzzi, Luca; Diotallevi, Aurora; Bocconcelli, Matteo; Donati, Maria Alice; Barone, Rita; Guerrini, Renzo; Jaeken, Jaak; Stocchi, Vilberto; Barbieri, ElenaDi Patria, Laura; Annibalini, Giosuè; Morrone, Amelia; Ferri, Lorenzo; Saltarelli, Roberta; Galluzzi, Luca; Diotallevi, Aurora; Bocconcelli, Matteo; Donati, Maria Alice; Barone, Rita; Guerrini, Renzo; Jaeken, Jaak; Stocchi, Vilberto; Barbieri, Elen

Effects of a commercially available branched-chain amino acid-alanine-carbohydrate-based sports supplement on perceived exertion and performance in high intensity endurance cycling tests

Background:Sports nutritional supplements containing branched-chain amino acids (BCAA) have been widelyreported to improve psychological and biological aspects connected to central fatigue and performance inendurance exercise, although the topic is still open to debate. The aim of the present study was to determinewhether the intake of a commercially available BCAA-based supplement, taken according to the manufacturer’srecommendations, could affect the rating of perceived exertion (RPE) and performance indexes at the beginning(1d) and end of a 9-week (9w) scheduled high intensity interval training program, with an experimental approachintegrating the determination of psychometric, performance, metabolic and blood biochemical parameters.Methods:This was a randomized double-blind placebo-controlled study. Thirty-two untrained, healthy young adults(20 males and 12 female) were enrolled. A high-intensity endurance cycling (HIEC) test was used to induce fatigue inthe participants: HIEC consisted in ten 90 s sprints interspersed by ten 3 min recovery phases and followed by a finalstep time to exhaustion was used. In parallel with RPE, haematological values (creatine kinase, alanine, BCAA,tryptophan, ammonia and glucose levels), and performance indexes (maximal oxygen consumption - VO2max,powerassociated with lactate thresholds - WLT1,WLT2and time to exhaustion - TTE) were assessed. All subject took thesupplement (13.2 g of carbohydrates; 3.2 g of BCAA and 1.6 g of L-alanine per dose) or placebo before each test andtraining session. Dietary habits and training load were monitored during the entire training period.Results:The administration of the supplement (SU) at 1d reduced RPE by 9% during the recovery phase, as comparedto the placebo (PL); at 9w the RPE scores were reduced by 13 and 21% during the sprint and recovery phase,respectively; at 9w, prolonged supplement intake also improved TTE and TRIMP. SU intake invariably promoted a rapidincrease (within 1 h) of BCAA serum blood levels and prevented the post-HIEC tryptophan: BCAA ratio increase foundin the PL group, at both 1d and 9w. There was no difference in dietary habits between groups and those habits didnot change over time; no difference in glycemia was found between SU and PL. VO2max,WLT1and WLT2valuesimproved over time, but were unaffected by supplement intake. Conclusions:On the whole, these results suggest that i) the intake of the BCAA-based commercially availablesupplement used in this study reduces RPE as a likely consequence of an improvement in the serum tryptophan: BCAAratio; ii) over time, reduced RPE allows subjects to sustain higher workloads, leading to increased TRIMP and TTE

Effects of a Home-Based Lifestyle Intervention Program on Cardiometabolic Health in Breast Cancer Survivors during the COVID-19 Lockdown

This study aimed to evaluate the cardiometabolic effects of a home-based lifestyle intervention (LI) in breast cancer survivors (BCSs) during the COVID-19 lockdown. In total, 30 BCSs (women; stages 0-II; non-metastatic; aged 53.5 ± 7.6 years; non-physically active; normal left ventricular systolic function) with a risk factor for recurrence underwent a 3-month LI based on nutrition and exercise. Anthropometrics, Mediterranean diet adherence, physical activity level (PAL), cardiorespiratory fitness (VO2max), echocardiographic parameters, heart rate variability (average standard deviation of NN intervals (ASDNN/5 min) and 24 h very- (24 hVLF) and low-frequency (24 hLF)), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein (hs-CRP)) were evaluated before (T0) and after (T1) the LI. After the LI, there were improvements in: body mass index (kg/m2: T0 = 26.0 ± 5.0, T1 = 25.5 ± 4.7; p = 0.035); diet (Mediet score: T0 = 6.9 ± 2.3, T1 = 8.8 ± 2.2; p < 0.001); PAL (MET-min/week: T0 = 647 ± 547, T1 = 1043 ± 564; p < 0.001); VO2max (mL·min-1·kg-1: T0 = 30.5 ± 5.8, T1 = 33.4 ± 6.8; p < 0.001); signs of diastolic dysfunction (participants: T0 = 15, T1 = 10; p = 0.007); AS-DNN/5 min (ms: T0 = 50.6 ± 14.4, T1 = 55.3 ± 16.7; p = 0.032); 24 hLF (ms2: T0 = 589 ± 391, T1 = 732 ± 542; p = 0.014); glycemia (mg/dL: T0 = 100.8 ± 11.4, T1 = 91.7 ± 11.0; p < 0.001); insulin resistance (HOMA-IR score: T0 = 2.07 ± 1.54, T1 = 1.53 ± 1.11; p = 0.005); testosterone (ng/mL: T0 = 0.34 ± 0.27, T1 = 0.24 ± 0.20; p = 0.003); hs-CRP (mg/L: T0 = 2.18 ± 2.14, T1 = 1.75 ± 1.74; p = 0.027). The other parameters did not change. Despite the home-confinement, LI based on exercise and nutrition improved cardiometabolic health in BCSs

Muscle and Systemic Molecular Responses to a Single Flywheel Based Iso-Inertial Training Session in Resistance-Trained Men

Growing evidence points to the effectiveness of flywheel (FW) based iso-inertial resistance training in improving physical performance capacities. However, molecular adaptations induced by FW exercises are largely unknown. Eight resistance-trained men performed 5 sets of 10 maximal squats on a FW device. Muscle biopsies (fine needle aspiration technique) and blood samples were collected before (t0), and 2 h (t1) after FW exercise. Blood samples were additionally drawn after 24 h (t2) and 48 h (t3). Paired samples t-tests revealed significant increases, at t1, of mRNA expression of the genes involved in inflammation, in both muscle (MCP-1, TNF-α, IL-6) and peripheral blood mononuclear cells (IkB-α, MCP-1). Circulating extracellular vesicles (EVs) and EV-encapsulated miRNA levels (miR-206, miR-146a) significantly increased at t1 as well. Conversely, muscle mRNA level of genes associated with muscle growth/remodeling (IGF-1Ea, cyclin D1, myogenin) decreased at t1. One-way repeated measure ANOVAs, with Bonferroni corrected post-hoc pairwise comparisons, revealed significant increases in plasma concentrations of IL-6 (t1; t2; t3) and muscle creatine kinase (t1; t2), while IGF-1 significantly increased at t2 only. Our findings show that, even in experienced resistance trained individuals, a single FW training session modifies local and systemic markers involved in late structural remodeling and functional adaptation of skeletal muscle

Mitohormesis in muscle cells: a morphological, molecular, and proteomic approach

Low-level oxidative stress induces an adaptive response commonly defined as hormesis; this type of stress is often related to reactive oxygen species (ROS) originating from the mitochondrial respiratory chain (mitochondrial hormesis or mitohormesis). The accumulation of transient low doses of ROS either through chronic physical activity or caloric restriction influences signaling from the mitochondrial compartment to the cell, reduces glucose metabolism, induces mitochondrial metabolism, increases stress resistance and ultimately, increases lifespan. Mitochondrial formation of presumably harmful levels (chronic and/or excessive) of ROS within skeletal muscle has been observed in insulin resistance of obese subjects, type 2 diabetes mellitus, as well as in impaired muscle function associated with normal aging. Advances in mitochondrial bioimaging combined with mitochondrial biochemistry and proteome research have broadened our knowledge of specific cellular signaling and other related functions of the mitochondrial behavior. In this review, we describe mitochondrial remodeling in response to different degrees of oxidative insults induced in vitro in myocytes and in vivo in skeletal muscle, focusing on the potential application of a combined morphological and biochemical approach. The use of such technologies could yield benefits for our overall understanding of physiology for biotechnological research related to drug design, physical activity prescription and significant lifestyle change

Altered muscle mitochondrial, inflammatory and trophic markers, and reduced exercise training adaptations in type 1 diabetes

Growing evidence of impaired skeletal muscle health in people with type 1 diabetes points toward the presence of a mild myopathy in this population. However, this myopathic condition is not yet well characterised and often overlooked, even though it might affect the whole-body glucose homeostasis and the development of comorbidities. This study aimed to compare skeletal muscle adaptations and changes in glycaemic control after 12 weeks of combined resistance and aerobic (COMB) training between people with type 1 diabetes and healthy controls, and to determine whether the impaired muscle health in type 1 diabetes can affect the exercise-induced adaptations. The COMB training intervention increased aerobic capacity and muscle strength in both healthy and type 1 diabetes sedentary participants, although these improvements were higher in the control group. Better glucose control, reduced glycaemic fluctuations and fewer hypoglycaemic events were recorded at post- compared to pre-intervention in type 1 diabetes. Analysis of muscle biopsies showed an alteration of muscle markers of mitochondrial functions, inflammation, ageing and growth/atrophy compared to the control group. These muscular molecular differences were only partially modified by the COMB training and might explain the reduced exercise adaptation observed in type 1 diabetes. In brief, type 1 diabetes impairs many aspects of skeletal muscle health and might affect the exercise-induced adaptations. Defining the magnitude of diabetic myopathy and the effect of exercise, including longer duration of the intervention, will drive the development of strategies to maximise muscle health in the type 1 diabetes population