Modern understanding of the role of calpains in muscles

Corresponding authors: Shu-yu Yang, Xiamen Diabetes Institute, Department of Endocrinology and Metabolism, The First Hospital of Xiamen, Xiamen University, 55 Zhenhai Road, Xiamen 361003, China ( xmyangshuyu@126.com). Jiang He, MD, PhD, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal St, Ste 2000, New Orleans, LA 70112 ( jhe@tulane.edu ). Xiao-Ying Li, MD, PhD, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025 (lixy@sibs.ac.cn). Introduction: Nonalcoholic fatty liver disease (NAFLD) and its cardiovascular complications are common public health problems. Hypothesis: Although the benefit of exercise on NAFLD and cardiometabolic risk factors is documented, the effects of intensive and moderate exercise on these outcomes have not been thoroughly investigated.. Methods: We conducted a randomized controlled trial among 220 individuals aged 40-65 years with a waist circumference of ≥90 cm in men and ≥85 cm in women. NAFLD was defined by proton magnetic resonance spectroscopy (1H-MRS). Participants were randomly assigned to the intensive exercise group (vigorous exercise at 65-80% maximum oxygen consumption by running on a treadmill 30 min/day and 5 days/week for 6 months, followed by moderate exercise by brisk walking 150 min/week for another 6 months), the moderate exercise group (brisk walking 150 min/week for the entire 12 months), or the usual care control (lifestyle counseling for 12 months). The primary outcome was the change of intra-hepatic triglyceride content as determined by 1 H-MRS. Secondary outcomes were metabolic risk factors. Results: At 12 months, the mean change of intra-hepatic triglyceride content from baseline was -6.10% in the intensive exercise, -5.91% in the moderate exercise, and -2.73% in the control groups (P<0.0001). Compared to the control group,the intensive and moderate exercise groups had significant net reductions of intra-hepatic triglyceride content at 6 months (-4.56%, 95% CL-6.71 to -2.42, p<0.001 for intensive and -3.86%, 95% CL-6.01 to -1.71, p<0.001 for moderate) and 12 months (-3.37%, 95% CL-5.52 to -1.22, p<0.001 for intensive, and -3.19%, 95% CL-5.34 to -1.04, p<0.001 for moderate). The net changes of intra-hepatic triglyceride content were not significantly different between the two exercise groups. Both intensive and moderate exercise reduced waist circumference, body weight, and blood pressure; additionally, intensive exercise reduced body fat mass, visceral fat, and body fat percent. Conclusions: Moderate intensity and vigorous intensity exercise were equally effective in improving NAFLD and blood pressure while vigorous exercise produced greater reductions of body fat.

The root of the matter: nitrate-rich beetroot juice reduces skeletal muscle O2 uptake during exercise.

Advances in exercise, physical activity, and diabetes mellitus.

The attenuation of postprandial lipemia by aerobic exercise depends on allelic variations of the Apolipoprotein B gene

According to classical concepts, the key markers of inflammation both in the body and in the muscles are cytokines such as IL-6 and IL-10. They are able to have both pro-inflammatory and anti-inflammatory effects in muscle fiber. For example, it note that after intense physical exercise, an increase in the concentration of IL-6 mRNA in monocytes was observed and did not increase after exercise, indicating that the increase in IL-6 levels during exercise is due to activation not of immune cells, but in the skeletal muscles themselves. However, later a series of experimental studies proved that even after the restoration of the normal cytokine profile in the muscles because of severe overtraining, performance also remained at a low level. As a result, it suggested that cytokines are not a limiting factor in the development of inflammation, but are part of complex functional systems, since they can produced not only during physical activity. Therefore, a current direction in sports physiology is the study of the mechanisms of development of inflammatory reactions, as well as the search for new informative markers. In accordance with this, we conducted a literature analysis, the purpose of which is to identify and substantiate new informative markers involved in the inflammatory response in muscles. This literature review examines both the classical mechanisms of the development of the inflammatory response, based on the cytokine theory, and examines new possible elements that can play a significant role in the development of this process. For example, due to an uncontrolled increase in calcium concentration during intense physical activity, calpains activated, which can cause the destruction of protein structures in muscles. Therefore, a local inflammatory reaction may occur. This effect may significantly enhanced by NF-κB, which causes muscle disturbances by increasing the transcription of muscle-specific ubiquitin ligases, as well as regulating the expression of a number of inflammatory molecules. It should also note that NF-κB is one of the activators of inducible nitrogen synthase (iNOS) in the first stages of inflammation in muscle without the participation of macrophages. Increased production of i-NOS under conditions of disruption of physiological processes in the cell will contribute to the aggravation of oxidative stress and further cellular destabilization. The resulting overproduction of NO and large amounts of ROS within the cell may contribute to the formation of the toxic molecule peroxynitrite (ONOO-). Peroxynitrite, due to its oxidative abilities, can affect the membrane of both the cell itself and the plasma reticulum, thereby causing an additional influx of exogenous calcium and release of endogenous calcium into the cytosol, aggravating this pathological process several times.An interesting aspect to study is the role of the nervus vagus (vagus nerve) in the development of inflammation in the muscle, which is one of the key regulators of the inflammatory process in the body. Thus, according to separate studies, it found that vagus nerve stimulation (VNS) reduces the release of pro-inflammatory cytokines during acute inflammation. This effect called the “cholinergic anti-inflammatory pathway.” However, its role in the regulation of muscle inflammation has poorly studied, so further study of its role in inflammation processes is an urgent scientific direction with the aim of possible use as a therapeutic platform for the correction of disorders after exposure to prolonged physical activity. It is important to emphasize that the inflammatory response in muscles in response to physical activity is a complex dynamic system in which a shift in one direction can lead to the development of a hyperimmune response or, on the contrary, reduce it. Therefore, understanding this process, as well as identifying trigger mechanisms, will in the future make it possible to increase not only the effectiveness of the training process, but also to prevent the development of pathological conditions.

Objective To investigate the clinical features of patients with rhabdomyolysis and acute kidney injury (AKI) caused by intense exercise. Methods Data on patients with rhabdomyolysis and AKI due to intense military exercise from January 2002 to December 2017 in a single Chinese nephrology center were retrospectively reviewed. Parameters included clinical manifestations, markers of renal function and muscle damage, treatment and prognosis. Results Twenty-two male servicemen with AKI caused by rhabdomyolysis were included. They took part in the military running training before onset. 95.5%(21/22) took part in 5-kilometer race, of which cross-country was 86.4% (19 cases) and bare-handed was 9.1% (2 cases). Most cases occurred in summer, in which 72.7% (16 cases) took part in 5-kilometer cross-country race. The levels of serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA) and creatine kinase (CK) significantly increased in patients, with 9.1% (2 cases) reaching AKI stage 1, 31.8% (7 cases) reaching AKI stage 2, and 59.1% (13 cases) reaching AKI stage 3, respectively. Serum CK levels were positively correlated with AKI stage (r=0.453, P<0.05), Scr (r=0.494, P<0.05) and BUN (r=0.545, P<0.01), while negatively correlated with UA (r=- 0.487, P<0.05). Serum LDH levels were positively correlated only with age (r=0.533, P<0.05). Serum UA presented inverse correlations with BUN (r=- 0.513, P<0.05), K+ (r=- 0.642, P<0.01) and CK (r=- 0.487, P<0.05), and positive correlation with age (r=0.431, P<0.05). In particular, duration from onset of disease had a stronger positive association with BUN (r=0.907, P<0.01) and Scr (r=0.690, P<0.01). Of these patients with AKI, 21 cases(95.5%) reached complete recovery of kidney function and 1 case (4.5%) changed to chronic renal failure within 3 months after comprehensive treatments, including 8 cases(36.4%) who received appropriate continuous venovenous hemofiltration. Conclusions Intense exercise in summer is likely to cause rhabdomyolysis and AKI. Early diagnosis and comprehensive treatment including appropriate blood purification are crucial for a successful treatment. Our findings also emphasize the importance of age on muscle injury and the monitoring of electrolysts, markers of muscle damage and renal function for prevention of rhabdomyolysis and its related complications. Key words: Rhabdomyolysis; Acute kidney injury; Intense exercise; Blood purification

The analgesic and psychoactive effects of exercise (EX) are well established. Despite this, the EX intensity needed to elicit an optimal effect on these phenomena is unknown. PURPOSE: To compare the effect of EX intensity on post EX analgesia and subjective psychoactive mood state. METHODS: Six subjects (1 male; 5 females; age = 20.6 ± 0.8 yrs) were tested for maximal aerobic exercise capacity (VO2max) using a graded cycling test. Following the VO2max, each subject was studied once a week using control conditions or 45%, 65% and 75%-85% of their VO2max in randomized order. Each EX bout lasted 30 mins and consisted of a 5-min warm-up, 20-mins at the assigned EX workload and a 5-min cooldown. The control session consisted of 30-mins of sitting on a cycle with no EX. EX analgesia was assessed by finding minimal pain threshold (MPT) before and following EX using a pain algometer on the extensor carpi radialis and was measured in Newtons (N). The Psychoactive Effects Questionnaire (PEQ), comprised of 36 questions that assess the subjective dopaminergic effects associated with the effects psychoactive drugs, was administered before and after EX. Blood lactate (BL) was also assessed at the same timepoints as MPT and PEQ. Breath by breath oxygen consumption was measured during EX using indirect calorimetry. Change in (Δ) MPT and PEQ (PreEX vs PostEX) was quantified using a two-tailed Student’s T-Test. The effect of EX intensity on MPT and PEQ was assessed by a one-way repeated measures ANOVA. Data are shown as mean ± SEM. RESULTS: BL increased in a linear fashion in response to increased EX intensity (R = 0.50; p < 0.001). Control MPT was 29.8 ± 2.1 N. There was a change in MPT, following each EX session (Control vs. 45% = 37.6 ± 1.4; 65% = 39.5 ± 0.5; 85% = 42.9 ± 1.1; p < 0.05). EX at 75%-85% had a greater impact on MPT relative to the 45% (85% = 13.02 ± 1.0 ∆N vs. 45% = 7.8 ± 1.5 ∆N; p < 0.05) session but not the 65% session (9.5 ± 1.5 ∆N; p > 0.05). There was no difference between the 45% and 65% EX session (p > 0.05). PEQ was significantly increased following EX by 118 ± 12.1% (p < 0.05). Unlike MPT, PEQ did not change dependent upon the intensity of the EX session (p < 0.05). CONCLUSION: Higher intensity EX (85% VO2max) appears to elicit a greater analgesic effect relative to lower intensity (45% VO2max). While EX increases PEQ it does not appear to be sensitive to EX intensity.

Introduction: The oxygen uptake kinetics of cyclists with  O2max values associated with Elite standards has not been investigated. A hypothesis was tested stating that trained cyclists have faster oxygen uptake responses as aerobic fitness increases. Methods: Participants (n = 16, combined group) completed a series of square wave 6-min exercises at moderate (80% LT), heavy (50%∆ between the power at LT and  O2max), and severe (power at  O2max) intensities. The  O2 response after the onset of exercise was described by a double exponential model. Participants were further assigned to a high fitness (HF, n = 8) group ( O2max 65 ± 4.7 ml min-1 kg-1) and a moderate fitness (MF, n = 8) group ( O2max 55.1 ± 4.8 ml min-1 kg-1). Results: Results showed a significant slowing of phase II response time (t) above the LT (P < 0.05), and a reduction in gain (G) during severe intensity exercise (P < 0.05). During heavy intensity exercise, t was moderately correlated with  O2max (r = -0.64, P < 0.1), and significant differences (P < 0.05) occurred between HF and MF groups. A significant difference also occurred in G between HF and MF groups (F = 5.6, P < 0.05) despite no change in the slow component. Conclusion: It was concluded that during heavy intensity exercise, the speed of oxygen uptake kinetics continued to improve with increasing aerobic fitness. The mechanism responsible was hypothesised to be related to the percentage of type I muscle fibres.

The stratified random sampling method was used to investigate 600 students in normal schools. Using SPSS25.0 statistical software, through descriptive analysis, independent sample t-test, one-way ANOVA, Pearson correlation analysis, hierarchical linear regression analysis, and other statistical methods, this paper explored the main factors affecting the physical exercise activities of students in normal schools. The results showed that: (1) The descriptive analysis showed that the physical exercise level of students in normal schools was relatively low, which was mainly shown as short exercise time, low exercise intensity, low exercise frequency, and small exercise amount. Besides, students in normal schools participate in physical exercise in a single form, mainly aerobic exercise, and their exercise intensity and exercise frequency need to be improved. (2) The independent sample t-test showed that there were significant differences in physical exercise level, exercise amount, and exercise intensity in terms of gender, major, and other demographic aspects of students in normal schools (P<0.01). Also, there was a significant difference in exercise time in terms of gender (P<0.01), and exercise intensity and exercise time appeared to be marginally significant in terms of grade (P<0.10). (3) The one-way ANOVA showed that with the improvement of physical exercise level, the scores of each dimension of reasons of students in normal schools participating in physical exercise showed a downward trend, which was especially obvious from zero exercise amount to medium exercise amount (P<0.01). (4) Pearson correlation analysis showed that there was a close relationship among the types of sports, the amount of physical exercise, and the reasons for participation in physical exercise. Enjoyment, physical fitness enhancement, muscle strength enhancement, and recreation were the main factors that affected students in normal schools participating in different sports and physical exercise. (5) The hierarchical regression analysis showed that demographic indicators and reasons for participation in physical exercise could be a significant predictor of the physical exercise level of students in normal schools. Among them, gender (β= — 0.203, P<0.01), enjoyment (β= — 0.346, P<0.01), and physique enhancement (β=—0.130, P<0.05) could play a negative predictive role, while the types of sports (β= 0.239, P<0.01), health promotion (β= 0.142, P<0.01), and recreation (β= 0.112, P<0.05) could play a significant positive predictive role. The research showed that gender, types of sports, and enjoyment were the core factors that affected the physical exercise of students in normal schools. Moreover, health promotion was the key factor affecting college students’ physical exercise, and physical fitness enhancement and recreation were the two important factors that affected physical exercise.

The purpose of the present study was to examine comprehensively the kinetics of oxygen uptake (VO2) during treadmill running across the moderate, heavy and severe exercise intensity domains. Nine subjects [mean (SD age, 27 (7) years; mass, 69.8 (9.0) kg; maximum VO2, VO2max, 4,137 (697) ml x min(-1)] performed a series of "square-wave" rest-to-exercise transitions of 6 min duration at running speeds equivalent to 80% and 100% of the VO2 at lactate threshold (LT; moderate exercise); and at 20%, 40%, 60%, 80% and 100% of the difference between the VO2 at LT and VO2max (delta heavy and severe exercise). Critical velocity (CV) was also determined using four maximal treadmill runs designed to result in exhaustion in 2-15 min. The VO2 response was modelled using non-linear regression techniques. As expected, the amplitude of the VO2 primary component increased with exercise intensity [from 1,868 (136) ml x min-( 1) at 80% LT to 3,296 (218) ml x min-(1) at 100% delta, P < 0.05]. However, there was a non-significant trend for the "gain" of the primary component to decrease as exercise intensity increased [181 (7) ml x kg(-1) x km(-1) at 80% LT to 160 (6) ml x kg(-1) x km(-1) at 100% delta]. The time constant of the primary component was not different between supra-LT running speeds (mean value range = 17.9-19.1 s), but was significantly shorter during the 80% LT trial [12.7 (1.4) s, P < 0 .05]. The VO2 slow component increased with exercise intensity from 139 (39) ml x min(-1) at 20% delta to 487 (57) ml x min(-1) at 80% delta (P < 0.05), but decreased to 317 (84) ml x min(-1) during the 100% delta trial (P < 0.05). During both the 80% delta and 100% delta trials, the VO2 at the end of exercise reached VOmax [4,152 (242) ml x min(-1) and 4,154 (114) ml x min(-1), respectively]. Our results suggest that the "gain" of the primary component is not constant as exercise intensity increases across the moderate, heavy and severe domains of treadmill running. These intensity-dependent changes in the amplitudes and kinetics of the VO2 response profiles may be associated with the changing patterns of muscle fibre recruitment that occur as exercise intensity increases.

INTRODUCTION Regulation of skeletal muscle protein mass is implicated not only in exercise performance but in metabolic health. Exercise in combination with nutrition, particularly dietary protein/amino acid intake, are the pragmatic approach that effectively induces muscle anabolic response (i.e., muscle hypertrophy) through regulating protein synthesis and breakdown. PURPOSE The purpose of this review was to summarize available data on the effect of exercise intervention and amino acids intake on muscle protein synthesis and breakdown and provide an insight into development of an effective exercise intervention and amino acids supplements, applicable to training practice. METHODS In this review, we have reviewed currently available data mainly from stable isotope tracer studies with respect to the effect of exercise intervention and protein or amino acid supplement on muscle protein anabolic response. CONCLUSIONS Taken together, exercise alone may not be effective in achieving a positive net muscle protein balance due to the fact that protein breakdown still exceeds protein synthesis until nutrition intake such as protein/amino acids. It appears that muscle anabolic response increases in proportional to the amount of protein intake up to 20 – 35 g depending on quality of protein, age, differences on exercise intensity, duration, and frequency, and individual’s training status. 색인어: ìš´ë™í›ˆë ¨, 단백질 섭취, 골격근 단백질 대사, ì•ˆì •ì„± 동위원소 ì¶”ì ì²´ë²• Keywords: Exercise, Protein intake, Skeletal muscle protein metabolism, Stable isotope tracer methodology

The relationship between habitual physical activity (PA) and experimental pain tolerance has been investigated in small samples of young, healthy and/or single-sex volunteers. We used a large, population-based sample to assess this relationship in men and women with and without chronic pain. We used data from the sixth and seventh Tromsø Study surveys (2007-2008; 2015-2016), with assessed pain tolerance of participants with the cold pressor test (CPT: dominant hand in circulating cold water at 3°C, maximum test time 106s), and self-reported total amount of habitual PA in leisure time (n=19,087), exercise frequency (n=19,388), exercise intensity (n=18,393) and exercise duration (n=18,343). A sub-sample had PA measured by accelerometers (n=4,922). We used Cox regression to compare CPT tolerance times between self-reported PA levels. For accelerometer-measured PA, we estimated hazard ratios for average daily activity counts, and for average daily minutes of moderate-to-vigorous PA done in bouts lasting 10min or more. Models were tested for PA-sex, and PA-chronic pain and PA-moderate-to-severe chronic pain interactions. Leisure-time PA, exercise intensity and exercise duration were positively associated with CPT tolerance (p<.001; p=.011; p<.001). More PA was associated with higher CPT tolerance. At high levels of leisure-time PA and exercise intensity, men had a significantly higher CPT tolerance than women. Accelerometer-measured PA was not associated with CPT tolerance. This study is one of the first to show that higher self-reported habitual PA was connected to higher experimental pain tolerance in a population-based sample, especially for men. This was not found for accelerometer-measured PA. This study finds that higher level of self-reported leisure-time physical activity is associated with increased cold pressor pain tolerance in a large population-based sample. Though present in both sexes, the association is strongest among men. Despite the robust dose-response relationship between pain tolerance and self-reported activity level, no such relationship was found for accelerometer-measured activity, reflecting a possible discrepancy in the aspect of physical activity measured. Though the study design does not permit causal conclusions, the findings suggest that increasing physical activity may increase pain tolerance in the general population.

Liraglutide for overweight and obesity

Data about effects of exercise training in adolescents with intellectual disability (ID) are very limited. This study investigated the effect of 2 different frequencies of the same intensity and total training volume of combined exercise training on indices of body composition, physical fitness, and lipid profile in overweight and obese adolescents with ID. A total of 45 overweight and obese adolescents with ID aged 14-22 years with a total IQ 45-70 received combined exercise training 3 times a week (CET3) for 30 sessions (10 weeks; n = 15), twice a week (CET2) for 30 sessions (15 weeks; n = 15), or no training (10 weeks; n = 15). Groups were matched for age, sex, and education form. Before and after the intervention period, indices of body composition, physical fitness and lipid profile have been evaluated. Compared to the control group, CET3 resulted in a significant improvement of physical fitness, obesity indices, and lipid profile of the participants. Comparing CET2 with CET3, no significantly different evolutions were noticed, except for lower limb strength in favor of exercising 3 times a week. In conclusion, exercising 2 times a week, which is more feasible and practical for participants and guidance, has the same health beneficial effects as 3 times per week in overweight and obese adolescents with ID in short-term training.

Background and PurposeIrisin is an exercise-responsive myokine that has been proposed to exert anti-obesity benefits; yet its response during exercise in obese women is not described. This study characterized plasma irisin levels during a single bout of afternoon isocaloric-exercise of different intensities (moderate- vs high-intensity) in obese females.MethodsEleven obese females participated in 3 randomized study days beginning at 1600h: 1) no exercise (NoEx), 2) moderate exercise (ModEx; 55%VO2max) and 3) high intensity interval exercise (IntEx; 4 min (80%VO2max)/3 min (50% VO2max). Frequent blood samples were analyzed for glucose and lactate (whole-blood), and insulin, c-peptide, glucagon, and irisin (plasma) throughout 190 min of testing.ResultsPlasma irisin increased above baseline during ModEx and IntEx (P<0.05), but not NoEx (P>0.05). Peak irisin levels during ModEx and IntEx exercise were 11.9± 3.4% and 12.3 ± 4.1% relative to baseline (P<0.05), respectively, with no differences between exercise intensities (P>0.05). Irisin levels remained elevated above resting for 125 minutes post-exercise during ModEx, whereas levels returned to baseline within 15 minutes post-exercise during IntEx. Similarly, no associations were found between plasma irisin levels and circulating lactate, glucose, insulin, c-peptide, or glucagon among study days (P>0.05). However, there was an inverse association between basal irisin and lean mass (r = -0.70, P = 0.01).ConclusionA single bout of moderate and high intensity afternoon exercise induces modest increases in circulating irisin concentrations during exercise; however the regulation post-exercise appears to be dimorphic between exercise intensity in obese females. Future studies are needed to compare morning and afternoon exercise on irisin secretion.