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Key Points: Muscle-derived thermogenesis during acute cold exposure in humans consists of a combination of cold-induced increases in skeletal muscle proton leak and shivering. Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold-induced skeletal muscle proton leak and shivering intensity. Improved coupling between electromyography-determined muscle activity and whole-body heat production following cold acclimation suggests a maintenance of ATPase-dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis. Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure., Abstract: We previously showed that 4 weeks of daily cold exposure in humans can increase brown adipose tissue (BAT) volume by 45% and oxidative metabolism by 182%. Surprisingly, we did not find a reciprocal reduction in shivering intensity when exposed to a mild cold (18°C). The present study aimed to determine whether changes in skeletal muscle oxidative metabolism or shivering activity could account for these unexpected findings. Nine men participated in a 4 week cold acclimation intervention (10°C water circulating in liquid-conditioned suit, 2 h day -1 , 5 days week -1 ). Shivering intensity and pattern were measured continuously during controlled cold exposure (150 min at 4 °C) before and after the acclimation. Muscle biopsies from the m. vastus lateralis were obtained to measure oxygen consumption rate and proton leak of permeabilized muscle fibres. Cold acclimation elicited a modest 21% (P < 0.05) decrease in whole-body and m. vastus lateralis shivering intensity. Furthermore, cold acclimation abolished the acute cold-induced increase in proton leak. Although daily cold exposure did not change the fibre composition of the m. vastus lateralis, fibre composition was a strong predictor of the shivering pattern evoked during acute cold. We conclude that muscle-derived thermogenesis during acute cold exposure in humans is not only limited to shivering, but also includes cold-induced increases in proton leak. The efficiency of muscle oxidative phosphorylation improves with cold acclimation, suggesting that reduced muscle thermogenesis occurs through decreased proton leak, in addition to decreased shivering intensity as BAT capacity and activity increase. These changes occur with no net difference in whole-body thermogenesis., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

The effects of 2 different weight training programs incorporating bench press (BP) and pullover (PO) exercises on swimming performance, power, enzyme activity, and fiber type distribution were studied on 16 men (age = 23 ± 4 years). A 30-second group (n = 6) performed up to 20 repetitions of BP and PO in 30 seconds. The 2-minute group (n = 6) performed a maximum of 80 repetitions of BP and PO in 2 minutes. As participants reached the prescribed 20 or 80 repetitions, the weight was increased 4.5 kg. A third group (n = 4) served as nontraining controls. Exercise groups trained 3 times per week for 6 weeks. Maximal effort swims of 50 and 200 yd were performed before and after training. Training resulted in increases in work on both exercises in both groups pre- to post-training (BP 30 seconds, 722 ± 236-895 ± 250 kg; PO 30 seconds, 586 ± 252-1,090 ± 677 kg; and BP 2 minutes, 1,530 ± 414-1,940 ± 296; PO 2 minutes, 1,212 ± 406-2,348 ± 194, p ≤ 0.05). Swim performances of the 30-second group improved for both the 50-yd (32.0 ± 6.9 seconds, 30.0 ± 5.9 seconds, p ≤ 0.05) and 200-yd swims 200.0 ± 54 seconds, 182 ± 45.1 seconds (p ≤ 0.05), whereas 2-minute training improved only the 200-yd swim (198.3 ± 32.3 seconds, 186.2 ± 32.2 seconds). No changes in swim performance were observed for the control group. Triceps muscle succinate dehydrogenase activities increased (pre 3.48 ± 1.1 μmol · g(-1) wet weight per minute, post 6.25 ± 1.5 μmoles · g(-1) wet weight per minute, p ≤ 0.05) in only the 30-second training group, whereas phosphofructokinase activities and fiber type distribution did not change in either training group. This study has demonstrated that a 30-second 20-repetition weight training program, specific to the swimming musculature without concurrent swim training, improves swimming performances at both 50- and 200-yd distances.

Aging results in significant loss of mass and function of the skeletal muscle, which negatively impacts the quality of life. In this study we investigated whether aerobic exercise training has the potential to alter anabolic and catabolic pathways in the skeletal muscle. Five and twenty eight month old rats were used in the study. Aging resulted in decreased levels of follistatin/mTOR/Akt/Erk activation and increased myostatin/Murf1/2, proteasome subunits, and protein ubiquitination levels. In addition, TNF-α, reactive oxygen species (ROS), p53, and Bax levels were increased while Bcl-2 levels were decreased in the skeletal muscle of aged rats. Six weeks of exercise training at 60% of VO2max reversed the age-associated activation of catabolic and apoptotic pathways and increased anabolic signaling. The results suggest that the age-associated loss of muscle mass and cachexia could be due to the orchestrated down-regulation of anabolic and up-regulation of catabolic and pro-apoptotic processes. These metabolic changes can be attenuated by exercise training., (Copyright © 2015. Published by Elsevier Inc.)

We hypothesized that high altitude exposure and physical activity associated with the attack to Mt Everest could alter mRNA levels of DNA repair and metabolic enzymes and cause oxidative stress-related challenges in human skeletal muscle. Therefore, we have tested eight male mountaineers (25-40 years old) before and after five weeks of exposure to high altitude, which included attacks to peaks above 8000m. Data gained from biopsy samples from vastus lateralis revealed increased mRNA levels of both cytosolic and mitochondrial superoxide dismutase. On the other hand 8-oxoguanine DNA glycosylase (OGG1) mRNA levels tended to decrease while Ku70 mRNA levels and SIRT6 decreased with altitude exposure. The levels of SIRT1 and SIRT3 mRNA did not change significantly. However, SIRT4 mRNA level increased significantly, which could indicate decreases in fatty acid metabolism, since SIRT4 is one of the important regulators of this process. Within the limitations of this human study, data suggest that combined effects of high altitude exposure and physical activity climbing to Mt. Everest, could jeopardize the integrity of the particular chromosome., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A decline in mitochondrial biogenesis and mitochondrial protein quality control in skeletal muscle is a common finding in aging, but exercise training has been suggested as a possible cure. In this report, we tested the hypothesis that moderate-intensity exercise training could prevent the age-associated deterioration in mitochondrial biogenesis in the gastrocnemius muscle of Wistar rats. Exercise training, consisting of treadmill running at 60% of the initial Vo(2max), reversed or attenuated significant age-associated (detrimental) declines in mitochondrial mass (succinate dehydrogenase, citrate synthase, cytochrome-c oxidase-4, mtDNA), SIRT1 activity, AMPK, pAMPK, and peroxisome proliferator-activated receptor gamma coactivator 1-α, UCP3, and the Lon protease. Exercise training also decreased the gap between young and old animals in other measured parameters, including nuclear respiratory factor 1, mitochondrial transcription factor A, fission-1, mitofusin-1, and polynucleotide phosphorylase levels. We conclude that exercise training can help minimize detrimental skeletal muscle aging deficits by improving mitochondrial protein quality control and biogenesis.

Skeletal muscle hosts all of the isoforms of nitric oxide synthase (NOS). It is well documented that nitric oxide (NO) regulates force generation and satellite cell activation, and therefore, damage repair of skeletal muscle. NO can also activate nociceptors of C-fibers, thereby causing the sensation of pain. Although delayed-onset of muscle soreness (DOMS) is associated with decreased maximal force generation, pain sensation and sarcomere damage, there is a paucity of research linking NO and DOMS. The present mini-review attempts to elucidate the possible relationship between NO and DOMS, based upon current literature., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The metabolic syndrome (MetS) is a clustering of individual cardiovascular disease risk factors, which doubles the risk of early mortality. The authors' aimed to determine the prevalence and population attributable risk (PAR%) of the MetS among men according to demographic, physical, and lifestyle risk factors. A cross-sectional study was conducted in 1195 men in the Florey Adelaide Male Ageing Study, a regionally representative cohort of Australian men aged 35 to 81 years conducted in 2002-2005 (response rate, 45.1%). Prevalent MetS was determined according to the Adult Treatment Panel III (ATPIII) and International Diabetes Federation (IDF) classifications; and an extensive list of demographic, physical (including muscle strength, body composition by dual-energy x-ray absorptiometry, sex hormones), and lifestyle factors was accounted for. Prevalence estimates were 37.7% and 41.8% for ATPIII and IDF classifications. Odds ratios for present MetS were determined using multiple-adjusted logistic regression. Odds for present ATPIII MetS decreased (in order of importance) for lower insulin and increased for lower muscle mass, lower strength, and 3+ medical conditions. Odds for present IDF MetS decreased for lower insulin and increased for lower muscle mass, strength, and sex hormone-binding globulin levels; older age; and being married. Significant PAR% due to lowest insulin, muscle mass, and strength quarters were -44%, 27%, and 17% for the ATPIII Met, and -48%, 31%, and 20% for the IDF MetS. A substantial proportion of MetS cases would have been theoretically prevented if prior exposure to low muscle mass and strength were eradicated (PAR% ranged from 14% to 24%). Findings indicate that insulin resistance is a central abnormality in the MetS and that muscle mass and strength are strong protective factors independent of insulin resistance and abdominal fat accumulation. If confirmed prospectively, increases in muscle mass and strength needed to prevent a substantial proportion of MetS cases would be achievable with a short-term strength training intervention.

Background: Age-related change in body composition is associated with adverse health outcomes, including functional decline, disability, morbidity, and early mortality. Prevention of age-related changes requires a greater understanding of the associations among age, lifestyle factors, and body composition., Objective: We aimed to comprehensively determine lifestyle factors associated with age-related differences in body composition assessed by using dual-energy X-ray absorptiometry., Design: We analyzed baseline (cross-sectional) data collected from 2002 to 2005 for approximately 1200 men in the Florey Adelaide Male Aging Study, a regionally representative cohort of Australian men aged 35-81 y., Results: Mean values for whole-body lean mass (LM) and areal bone mineral density (aBMD) decreased, whereas mean values for abdominal fat mass (FM) and whole-body and abdominal percentage FM (%FM) increased with age. No significant age-related differences were found for whole-body FM. Multiple adjusted odds of being in the highest tertiles for whole-body and abdominal %FM decreased for smokers (63-71%) but increased with age group and for lowest energy (43-50%), carbohydrate (92-107%), and fiber (107%) intake tertiles. Multiple adjusted odds of being in the highest aBMD tertile decreased for lowest body mass (92%) and carbohydrate intake (63%) tertiles and for men aged > or = 75 y (78%) but increased for Australian birth (58%) and for participation in vigorous physical activities (82%)., Conclusions: Age-related differences in body composition indicate that whole-body FM remains stable but increases viscerally and that whole-body %FM is confounded by LM, whereas aBMD decreases with age. Age-related differences in %FM and aBMD are associated with demographic and lifestyle factors.

Exercise training, like diazepam, is commonly employed as a means of reducing anxiety. Both diazepam and exercise training have been shown to modify carbohydrate and lipid metabolism as well as influence calcium metabolism in skeletal muscle. As receptor binding and thereby efficacy of diazepam has been demonstrated to be modulated by the lipid environment of the receptor, and changes in calcium levels can affect a number of intracellular signalling pathways, we sought to determine if the interaction of both chronic diazepam and exercise training would modify selected metabolic indices in an animal model. For this purpose, muscle and liver glycogen, blood glucose and plasma free fatty acids (FFA) were measured in sedentary, exercise trained and exercise trained, acutely exhausted animals. Alterations in lipid and carbohydrate metabolism were observed in all experimental groups. Diazepam treatment alone exerts metabolic consequences, such as elevated muscle glycogen and plasma FFA and depressed blood glucose levels, which are similar to those observed with exercise training. When animals are acutely exercised to exhaustion, however, differences appear, including a reduced rise in plasma FFA, which suggests that long-term diazepam treatment does influence exercise metabolism, possibly as a result of effects on the sympatho-adrenal system.

Exercise increases the generation of reactive oxygen and nitrogen species (RONS) and by causing adaptation, could decrease the incidence of RONS-associated diseases. A single bout of exercise, depending upon intensity and duration, can cause an increase in antioxidant enzyme activity, decrease levels of thiols and antioxidant vitamins, and result in oxidative damage as a sign of incomplete adaptation. Increased levels of RONS and oxidative damage are initiators of a specific adaptive response, such as the stimulation of the activation of antioxidant enzymes, thiols, and enhanced oxidative damage repair. Regular exercise has the capability to develop compensation to oxidative stress, resulting in overcompensation against the increased level of RONS production and oxidative damage. Regular exercise causes adaptation of the antioxidant and repair systems, which could result in a decreased base level of oxidative damage and increased resistance to oxidative stress.

Telomerase is a specialized ribonucleoprotein enzyme complex which prevents the loss of the telomere. The activity of telomerase can be up- and down-regulated by various oxidative stresses but the effect of physical exercise is not known, whereas the modifying effect of cancer on telomerase activity is well documented. In the first study, we investigated the effect of mild and strenuous exercise training on telomerase activity, assessed by a PCR ELISA kit. No alteration in telomerase activity was detected. In the second investigation, solid sarcoma cells were transplanted to control, exercise trained or exercise trained and still exercising mice. On the 16th day after the transplantation, the size of tumors in the exercise trained group was 72% and in the exercising group 57% (P < 0.05) of that in the controls. Telomerase activity and 8-hydroxy-2'-deoxyguanosine levels in the liver were not significantly altered by exercise and/or sarcoma. We conclude that mild and strenuous exercise training does not significantly affect the activity of telomerase in the systems studied. Exercise training during sarcoma significantly retards the development of tumors and could possibly serve as a positive adjunct to treatment.

Background: Researchers employing a variety of training methods have demonstrated a fast-to-slow fibre transformation in animal skeletal muscle. The observation as to whether this occurs in exercise trained humans is limited and equivocal., Experimental Design: to examine this issue, skeletal muscle from seven subjects who had participated in a decade or more of high intensity aerobic training (DT) and six nontrained (NT) subjects was obtained by muscle biopsy from the vastus lateralis muscle (VL) and subjected to a modified myofibrillar ATPase technique to identify muscle fibre types. Muscle tissue was histochemically treated by exposure to an alkaline preincubation (pH 9.9), an acid preincubation (pH 4.3 or 4.6) and the formate-KCI preincubation buffer (pH 4.54), previously employed in animal studies., Results: The formate-KCl preincubation medium identified all major fibre types at a single pH in human subjects. The percentage of type I fibres in DT was 70.9% vs 37.7% in NT (p<0.01), while the type IIa fibres in DT (25.3%) was much lower (p<0.01) than NT (51.8%). Surprisingly, type IIa fibres in the DT group displayed lesser oxidative staining intensity (p<0.01) than type IIa fibres from the NT group. Mean cross-sectional area of type I fibres for DT (6233.9+/-1421.7 microm2) was greater (p<0.05) than either type I (5746.8+/-1135.2 microm2) or II (5693.5+/-1214.6 microm2) from NT., Conclusions: The results revealed that endurance training may promote a transition from type II to type I muscle fibre types and occurs at the expense of the type II fibre population.

The oxygen flux into the mitochondria of skeletal muscle increases with exercise. However, the extent of oxidative damage to mitochondrial proteins of skeletal muscle has only been estimated. We studied the alteration of reactive carbonyl derivatives (RCD) in mitochondrial and cytosolic fractions of skeletal muscle following 9 weeks of swimming training in rats. The RCD content of mitochondria was significantly elevated compared with the cytosolic fraction of both control and exercised animals. Accumulation of RCD in muscle mitochondria of the exercised group was also significantly elevated (P < 0.05). On the other hand, alteration of the accumulation of RCD was not apparent in the cytosolic fraction of skeletal muscle. The activity of proteasome complex, however, was increased in the cytosolic fraction of exercised muscle (P < 0.05). The data suggest that mitochondria of skeletal muscle accumulate significantly larger amounts of RCD than the cytosolic fraction and the tendency of the accumulation varies in cell fractions. Exercise training increases the accumulation of protein damage in mitochondria of skeletal muscle but cytosolic proteins are protected by increased activity of proteasome complex and possibly by other antioxidant enzymes.

Carbonic anhydrase (CA) inhibition is associated with a lower plasma lactate concentration ([La(-)](pl)), but the mechanism for this association is not known. The effect of CA inhibition on muscle high-energy phosphates [ATP and phosphocreatine (PCr)], lactate ([La(-)](m)), and glycogen was examined in seven men [28 +/- 3 (SE) yr] during cycling exercise under control (Con) and acute CA inhibition with acetazolamide (Acz; 10 mg/kg body wt iv). Subjects performed 6-min step transitions in work rate from 0 W to a work rate corresponding to approximately 50% of the difference between the O(2) uptake at the ventilatory threshold and peak O(2) uptake. Muscle biopsies were taken from the vastus lateralis at rest, at 30 min postinfusion, at end exercise (EE), and at 5 and 30 min postexercise. Arterialized venous blood was sampled from a dorsal hand vein and analyzed for [La(-)](pl). ATP was unchanged from rest values; no difference between Con and Acz was observed. The fall in PCr from rest [72 +/- 3 and 73 +/- 3.6 (SE) mmol/kg dry wt for Con and Acz, respectively] to EE (51 +/- 4 and 46 +/- 5 mmol/kg dry wt for Con and Acz, respectively) was similar in Con and Acz. At EE, glycogen (mmol glucosyl units/kg dry wt) decreased to similar values in Con and Acz (307 +/- 16 and 300 +/- 19, respectively). At EE, no difference was observed in [La(-)](m) between conditions (46 +/- 6 and 43 +/- 5 mmol/kg dry wt for Con and Acz, respectively). EE [La(-)](pl) was higher during Con than during Acz (11.4 +/- 1.0 vs. 8.2 +/- 0.6 mmol/l). The similar [La(-)](m) but lower [La(-)](pl) suggests that the uptake of La(-) by other tissues is enhanced after CA inhibition.

Practitioners and scientists have demonstrated great interest in the physiological and biochemical effects of endurance training on the results of the marathon run. It is well documented that athletes with a large proportion of slow twitch and fast twitch aerobic skeletal muscle fibre, high metabolic enzyme activities and concentrations, large mitochondria concentration and, of course, the ability to increase the power output generated for a given rate of oxygen consumption and energy expenditure, are generally highly successful distance runners. Aerobic and endurance training have been shown to bring about significant adaptations to the skeletal muscle and its inclusions as well as to the delivery system. In particular, enzyme activity levels are readily mutable, mitochondrial concentrations increase, and some evidence suggests that the fibre distribution is changed. This article briefly reports on changes in skeletal muscle brought about by endurance training and those changes that appear most effective in yielding success in endurance events.

The present study was initiated to determine the time course of changes in the profile of selected skeletal muscle myofibril proteins during compensatory overload. Whole muscle isometric contractile properties were measured to assess the physiological consequences of the overload stimulus. Compensatory overload of plantaris muscle of rats was induced by surgical ablation of the synergistic soleus and gastrocnemius muscles. Myosin light chain (LC) and tropomyosin (TM) compositions of control (CP) and overloaded plantaris (OP) muscles were determined by electrophoresis and myofibrillar ATPase assays were performed to assess changes in contractile protein interactions. Within one week of overload decreases in the alpha:beta TM ratio and myofibrillar ATPase activity were observed. Following 30 days of overload, a transition in type II to type I fibres was associated with an increase in slow myosin LC1. Interestingly, after 77 days of overload, the TM subunit ratio returned to one resembling a fast twitch muscle. It is proposed that the early and transitory changes in the TM subunits of OP, as well as the rapid initial depression in maximum tetanic isometric force and myofibrillar ATPase activity may be explained as a result of muscle fibre degeneration-regeneration. We propose that alterations in protein expression induced by compensatory overload reflect both degenerative-regenerative change and increased neuromuscular activity.

The purpose of this study was to compare muscle oxidative capacity between moderately active young and old humans by measuring intracellular threshold (IT) during exercise with 31P-magnetic resonance spectroscopy (31P-MRS). Changes in phosphocreatine, inorganic phosphate, and intracellular pH were measured by 31P-MRS during a progressive unilateral ankle plantar flexion exercise protocol in groups of moderately active old (n = 12, mean age 66.7 years) and young (n = 13, mean age 26.2 years) individuals. From muscle biopsy samples of the lateral gastrocnemius, citrate synthase (CS) activity was determined in six subjects from each group, and fibre type composition was determined in nine old and ten young subjects. The old group had a lower IT for pH, as a percentage of peak work rate (P < 0.05), despite a similar CS activity compared to the young. IT was significantly correlated with CS activity (R = 0.59; P < 0.05), but not with fibre type composition. It was concluded that metabolic responses to exercise are affected by ageing, as indicated by a lower IT in old compared to young individuals.

Skeletal muscle biopsies (vastus lateralis) were performed in 12 patients (mean age 47 +/- 11 years) before and at 3 and 12 months after cardiac transplantation. Fiber type analysis revealed a predominance of type II fibers before cardiac transplantation (66 +/- 10%); the ratio did not change after transplantation. Fiber cross-sectional area increased by 35% to 39% in all fiber types by 12 months after cardiac transplantation. Fiber cross-sectional area, however, remained below the reported normal values. The number of capillaries surrounding each fiber did not change after cardiac transplantation. Skeletal muscle enzyme activity of phosphofructokinase, citrate synthase, and beta-hydroxyacyl coenzyme A dehydrogenase increased by 26%, 47%, and 63%, respectively, after cardiac transplantation (p < 0.05). Peak oxygen uptake also increased significantly after cardiac transplantation (19.5 +/- 8.1 ml/kg/min at 12 months vs 9.8 +/- 1.4 ml/kg/min before transplant, p < 0.01); however, uptake remained 40% below that of predicted. Thus, significant improvement in skeletal muscle morphology and biochemistry occurs in the first year after cardiac transplantation in association with improved exercise capacity. Recovery, however, may be incomplete, which could explain residual impairment of exercise capacity in these patients.

The effects of chronic diazepam (D) treatment and exercise training on total body mass (TBM), microsomal protein yield (MPY), calcium uptake by fragmented sarcoplasmic reticulum (SR), muscle fibre cross-sectional area, and both PFK and SDH activities were investigated in the tibialis anterior (TA), soleus (Sol), and plantaris (Plt) muscles of 50 male albino Sprague-Dawley rats. Rats were assigned randomly to control (C), sprint-trained (S), or endurance-trained (E) groups. Training was of 12 weeks duration. One-half of each group received daily intraperitoneally D doses of 5 mg kg-1 of TBM. Exercise reduced TBM (p < 0.05); increased the relative BM of the TA (E = 2.02 +/- 0.02, p < 0.01) and Plt (E = 1.15 +/- 0.02, p < 0.01; S = 1.13 +/- 0.03, p < 0.01), as well as the Ca++ uptake of the Sol SR (C = 0.08 +/- 0.02, E = 0.16 +/- 01, p < 0.05). MPY was elevated in S-Sol (C = 1.12 +/- 0.6, S = 1.52 +/- 0.1, p < 0.01). D elevated Sol MPY as well as TA PFK. S-trained animals had lower mean fibre areas than the E-trained (D-treated and untreated) animals. The elevated relative masses of TA and Plt are explained by a decreased TBM with exercise. The increased Ca++ uptake of the Sol indicates that E enhances this function, and the increased MPY probably implies an increased SR. The D could be responsible for the D-elevated Sol MPY as well as the TA PFK. El D did not reduce neuromuscular activity to a level adversely affecting oxidative enzyme activity, but in the case of PFK activity in the TA muscle, such a reduction was evident.