396 resultados para inspiratory muscle training


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Purpose Commencing selected workouts with low muscle glycogen availability augments several markers of training adaptation compared with undertaking the same sessions with normal glycogen content. However, low glycogen availability reduces the capacity to perform high-intensity (>85% of peak aerobic power (V·O2peak)) endurance exercise. We determined whether a low dose of caffeine could partially rescue the reduction in maximal self-selected power output observed when individuals commenced high-intensity interval training with low (LOW) compared with normal (NORM) glycogen availability. Methods Twelve endurance-trained cyclists/triathletes performed four experimental trials using a double-blind Latin square design. Muscle glycogen content was manipulated via exercise–diet interventions so that two experimental trials were commenced with LOW and two with NORM muscle glycogen availability. Sixty minutes before an experimental trial, subjects ingested a capsule containing anhydrous caffeine (CAFF, 3 mg-1·kg-1 body mass) or placebo (PLBO). Instantaneous power output was measured throughout high-intensity interval training (8 × 5-min bouts at maximum self-selected intensity with 1-min recovery). Results There were significant main effects for both preexercise glycogen content and caffeine ingestion on power output. LOW reduced power output by approximately 8% compared with NORM (P < 0.01), whereas caffeine increased power output by 2.8% and 3.5% for NORM and LOW, respectively, (P < 0.01). Conclusion We conclude that caffeine enhanced power output independently of muscle glycogen concentration but could not fully restore power output to levels commensurate with that when subjects commenced exercise with normal glycogen availability. However, the reported increase in power output does provide a likely performance benefit and may provide a means to further enhance the already augmented training response observed when selected sessions are commenced with reduced muscle glycogen availability. It has long been known that endurance training induces a multitude of metabolic and morphological adaptations that improve the resistance of the trained musculature to fatigue and enhance endurance capacity and/or exercise performance (13). Accumulating evidence now suggests that many of these adaptations can be modified by nutrient availability (9–11,21). Growing evidence suggests that training with reduced muscle glycogen using a “train twice every second day” compared with a more traditional “train once daily” approach can enhance the acute training response (29) and markers representative of endurance training adaptation after short-term (3–10 wk) training interventions (8,16,30). Of note is that the superior training adaptation in these previous studies was attained despite a reduction in maximal self-selected power output (16,30). The most obvious factor underlying the reduced intensity during a second training bout is the reduction in muscle glycogen availability. However, there is also the possibility that other metabolic and/or neural factors may be responsible for the power drop-off observed when two exercise bouts are performed in close proximity. Regardless of the precise mechanism(s), there remains the intriguing possibility that the magnitude of training adaptation previously reported in the face of a reduced training intensity (Hulston et al. (16) and Yeo et al.) might be further augmented, and/or other aspects of the training stimulus better preserved, if power output was not compromised. Caffeine ingestion is a possible strategy that might “rescue” the aforementioned reduction in power output that occurs when individuals commence high-intensity interval training (HIT) with low compared with normal glycogen availability. Recent evidence suggests that, at least in endurance-based events, the maximal benefits of caffeine are seen at small to moderate (2–3 mg·kg-1 body mass (BM)) doses (for reviews, see Refs. (3,24)). Accordingly, in this study, we aimed to determine the effect of a low dose of caffeine (3 mg·kg-1 BM) on maximal self-selected power output during HIT commenced with either normal (NORM) or low (LOW) muscle glycogen availability. We hypothesized that even under conditions of low glycogen availability, caffeine would increase maximal self-selected power output and thereby partially rescue the reduction in training intensity observed when individuals commence HIT with low glycogen availability.

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Resistance training results in skeletal muscle hypertrophy, but the molecular signalling mechanisms responsible for this altered phenotype are incompletely understood. We used a resistance training (RT) protocol consisting of three sessions [day 1 (d1), day 3 (d3), day 5 (d5)] separated by 48 h recovery (squat exercise, 4 sets × 10 repetitions, 3 min recovery) to determine early signalling responses to RT in rodent skeletal muscle. Six animals per group were killed 3 h after each resistance training session and 24 and 48 h after the last training session (d5). There was a robust increase in TNF? protein expression, and IKKSer180/181 and p38MAPK Thr180/Tyr182 phosphorylation on d1 (P < 0.05), which abated with subsequent RT, returning to control levels by d5 for TNF? and IKK Ser180/181. There was a trend for a decrease in MuRF-1 protein expression, 48 h following d5 of training (P = 0.08). Notably, muscle myofibrillar protein concentration was elevated compared to control 24 and 48 h following RT (P < 0.05). AktSer473 and mTORSer2448 phosphorylation were unchanged throughout RT. Phosphorylation of p70S6k Thr389 increased 3 h post-exercise on d1, d3 and d5 (P < 0.05), whilst phosphorylation of S6Ser235/236 increased on d1 and d3 (P < 0.05). Our results show a rapid attenuation of inflammatory signalling with repeated bouts of resistance exercise, concomitant with summation in translation initiation signalling in skeletal muscle. Indeed, the cumulative effect of these signalling events was associated with myofibrillar protein accretion, which likely contributes to the early adaptations in response to resistance training overload in the skeletal muscle.

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We examined acute molecular responses in skeletal muscle to repeated sprint and resistance exercise bouts. Six men [age, 24.7 ± 6.3 yr; body mass, 81.6 ± 7.3 kg; peak oxygen uptake, 47 ± 9.9 ml·kg -1 ·min -1; one repetition maximum (1-RM) leg extension 92.2 ± 12.5 kg; means ± SD] were randomly assigned to trials consisting of either resistance exercise (8 × 5 leg extension, 80% 1-RM) followed by repeated sprints (10 × 6 s, 0.75 N·m torque·kg -1) or vice-versa. Muscle biopsies from vastus lateralis were obtained at rest, 15 min after each exercise bout, and following 3-h recovery to determine early signaling and mRNA responses. There was divergent exercise order-dependent phosphorylation of p70 S6K (S6K). Specifically, initial resistance exercise increased S6K phosphorylation (?75% P < 0.05), but there was no effect when resistance exercise was undertaken after sprints. Exercise decreased IGF-I mRNA following 3-h recovery (?50%, P = 0.06) independent of order, while muscle RING finger mRNA was elevated with a moderate exercise order effect (P < 0.01). When resistance exercise was followed by repeated sprints PGC-1? mRNA was increased (REX1-SPR2; P = 0.02) with a modest distinction between exercise orders. Repeated sprints may promote acute interference on resistance exercise responses by attenuating translation initiation signaling and exacerbating ubiquitin ligase expression. Indeed, repeated sprints appear to generate the overriding acute exercise-induced response when undertaking concurrent repeated sprint and resistance exercise. Accordingly, we suggest that sprint-activities are isolated from resistance training and that adequate recovery time is considered within periodized training plans that incorporate these divergent exercise modes.

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The mammalian target of rapamycin (mTOR) is a highly conserved atypical serine-threonine kinase that controls numerous functions essential for cell homeostasis and adaptation in mammalian cells via 2 distinct protein complex formations. Moreover, mTOR is a key regulatory protein in the insulin signalling cascade and has also been characterized as an insulin-independent nutrient sensor that may represent a critical mediator in obesity-related impairments of insulin action in skeletal muscle. Exercise characterizes a remedial modality that enhances mTOR activity and subsequently promotes beneficial metabolic adaptation in skeletal muscle. Thus, the metabolic effects of nutrients and exercise have the capacity to converge at the mTOR protein complexes and subsequently modify mTOR function. Accordingly, the aim of the present review is to highlight the role of mTOR in the regulation of insulin action in response to overnutrition and the capacity for exercise to enhance mTOR activity in skeletal muscle.

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We examined acute molecular responses in skeletal muscle to divergent exercise stimuli by combining consecutive bouts of resistance and endurance exercise. Eight men [22.9 ± 6.3 yr, body mass of 73.2 ± 4.5 kg, peak O2 uptake (V?O2peak) of 54.0 ± 5.7 ml·kg-1·min-1] were randomly assigned to complete trials consisting of either resistance exercise (8 x 5 leg extension, 80% 1 repetition maximum) followed by a bout of endurance exercise (30 min cycling, 70% V?O2peak) or vice versa. Muscle biopsies were obtained from the vastus lateralis at rest, 15 min after each exercise bout, and after 3 h of passive recovery to determine early signaling and mRNA responses. Phosphorylation of Akt and Akt1Ser473 were elevated 15 min after resistance exercise compared with cycling, with the greatest increase observed when resistance exercise followed cycling (?55%; P < 0.01). TSC2-mTOR-S6 kinase phosphorylation 15 min after each bout of exercise was similar regardless of the exercise mode. The cumulative effect of combined exercise resulted in disparate mRNA responses. IGF-I mRNA content was reduced when cycling preceded resistance exercise (-42%), whereas muscle ring finger mRNA was elevated when cycling was undertaken after resistance exercise (?52%; P < 0.05). The hexokinase II mRNA level was higher after resistance cycling (?45%; P < 0.05) than after cycling-resistance exercise, whereas modest increases in peroxisome proliferator-activated receptor gamma coactivator-1? mRNA did not reveal an order effect. We conclude that acute responses to diverse bouts of contractile activity are modified by the exercise order. Moreover, undertaking divergent exercise in close proximity influences the acute molecular profile and likely exacerbates acute "interference".

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PURPOSE: We used gene microarray analysis to compare the global expression profile of genes involved in adaptation to training in skeletal muscle from chronically strength-trained (ST), endurance-trained (ET), and untrained control subjects (Con). METHODS: Resting skeletal muscle samples were obtained from the vastus lateralis of 20 subjects (Con n = 7, ET n = 7, ST n = 6; trained [TR] groups >8 yr specific training). Total RNA was extracted from tissue for two color microarray analysis and quantative (Q)-PCR. Trained subjects were characterized by performance measures of peak oxygen uptake V?O 2peak) on a cycle ergometer and maximal concentric and eccentric leg strength on an isokinetic dynamometer. RESULTS: Two hundred and sixty-three genes were differentially expressed in trained subjects (ET + ST) compared with Con (P < 0.05), whereas 21 genes were different between ST and ET (P < 0.05). These results were validated by reverse transcriptase polymerase chain reaction for six differentially regulated genes (EIFSJ, LDHB, LMO4, MDH1, SLC16A7, and UTRN. Manual cluster analyses revealed significant regulation of genes involved in muscle structure and development in TR subjects compared with Con (P < 0.05) and expression correlated with measures of performance (P < 0.05). ET had increased whereas ST had decreased expression of gene clusters related to mitochondrial/oxidative capacity (P ?‰Currency sign 0.05). These mitochondrial gene clusters correlated with V?O2peak (P < 0.05). V?O2peak also correlated with expression of gene clusters that regulate fat and carbohydrate oxidation (P < 0.05). CONCLUSION: We demonstrate that chronic training subtly coregulates numerous genes from important functional groups that may be part of the long-term adaptive process to adapt to repeated training stimuli.

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PURPOSE: Regulation of skeletal muscle mass is highly dependent on contractile loading. The purpose of this study was to examine changes in growth factor and inflammatory pathways following high-frequency resistance training. METHODS: Using a novel design in which male Sprague-Dawley rats undertook a "stacked" resistance training protocol designed to generate a summation of transient exercise-induced signaling responses (four bouts of three sets × 10 repetitions of squat exercise, separated by 3 h of recovery), we determined the effects of high training frequency on signaling pathways and transcriptional activity regulating muscle mass. RESULTS: The stacked training regimen resulted in acute suppression of insulin-like growth factor 1 mRNA abundance (P < 0.05) and Akt phosphorylation (P < 0.05), an effect that persisted 48 h after the final training bout. Conversely, stacked training elicited a coordinated increase in the expression of tumor necrosis factor alpha, inhibitor kappa B kinase alpha/beta activity (P < 0.05), and p38 mitogen-activated protein kinase phosphorylation (P < 0.05) at 3 h after each training bout. In addition, the stacked series of resistance exercise bouts induced an increase in p70 S6 kinase phosphorylation 3 h after bouts ×3 and ×4, independent of the phosphorylation state of Akt. CONCLUSIONS: Our results indicate that high resistance training frequency extends the transient activation of inflammatory signaling cascades, concomitant with persistent suppression of key mediators of anabolic responses. We provide novel insights into the effects of the timing of exercise-induced overload and recovery on signal transduction pathways and transcriptional activity regulating skeletal muscle mass in vivo.

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Skeletal muscle is a malleable tissue capable of altering the type and amount of protein in response to disruptions to cellular homeostasis. The process of exercise-induced adaptation in skeletal muscle involves a multitude of signalling mechanisms initiating replication of specific DNA genetic sequences, enabling subsequent translation of the genetic message and ultimately generating a series of amino acids that form new proteins. The functional consequences of these adaptations are determined by training volume, intensity and frequency, and the half-life of the protein. Moreover, many features of the training adaptation are specific to the type of stimulus, such as the mode of exercise. Prolonged endurance training elicits a variety of metabolic and morphological changes, including mitochondrial biogenesis, fast-to-slow fibre-type transformation and substrate metabolism. In contrast, heavy resistance exercise stimulates synthesis of contractile proteins responsible for muscle hypertrophy and increases in maximal contractile force output. Concomitant with the vastly different functional outcomes induced by these diverse exercise modes, the genetic and molecular mechanisms of adaptation are distinct. With recent advances in technology, it is now possible to study the effects of various training interventions on a variety of signalling proteins and early-response genes in skeletal muscle. Although it cannot presently be claimed that such scientific endeavours have influenced the training practices of elite athletes, these new and exciting technologies have provided insight into how current training techniques result in specific muscular adaptations, and may ultimately provide clues for future and novel training methodologies. Greater knowledge of the mechanisms and interaction of exercise-induced adaptive pathways in skeletal muscle is important for our understanding of the aetiology of disease, maintenance of metabolic and functional capacity with aging, and training for athletic performance. This article highlights the effects of exercise on molecular and genetic mechanisms of training adaptation in skeletal muscle.

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Introduction The culture in many team sports involves consumption of large amounts of alcohol after training/competition. The effect of such a practice on recovery processes underlying protein turnover in human skeletal muscle are unknown. We determined the effect of alcohol intake on rates of myofibrillar protein synthesis (MPS) following strenuous exercise with carbohydrate (CHO) or protein ingestion. Methods In a randomized cross-over design, 8 physically active males completed three experimental trials comprising resistance exercise (8×5 reps leg extension, 80% 1 repetition maximum) followed by continuous (30 min, 63% peak power output (PPO)) and high intensity interval (10×30 s, 110% PPO) cycling. Immediately, and 4 h post-exercise, subjects consumed either 500 mL of whey protein (25 g; PRO), alcohol (1.5 g·kg body mass−1, 12±2 standard drinks) co-ingested with protein (ALC-PRO), or an energy-matched quantity of carbohydrate also with alcohol (25 g maltodextrin; ALC-CHO). Subjects also consumed a CHO meal (1.5 g CHO·kg body mass−1) 2 h post-exercise. Muscle biopsies were taken at rest, 2 and 8 h post-exercise. Results Blood alcohol concentration was elevated above baseline with ALC-CHO and ALC-PRO throughout recovery (P<0.05). Phosphorylation of mTORSer2448 2 h after exercise was higher with PRO compared to ALC-PRO and ALC-CHO (P<0.05), while p70S6K phosphorylation was higher 2 h post-exercise with ALC-PRO and PRO compared to ALC-CHO (P<0.05). Rates of MPS increased above rest for all conditions (~29–109%, P<0.05). However, compared to PRO, there was a hierarchical reduction in MPS with ALC-PRO (24%, P<0.05) and with ALC-CHO (37%, P<0.05). Conclusion We provide novel data demonstrating that alcohol consumption reduces rates of MPS following a bout of concurrent exercise, even when co-ingested with protein. We conclude that alcohol ingestion suppresses the anabolic response in skeletal muscle and may therefore impair recovery and adaptation to training and/or subsequent performance.

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The aim of this study was to examine the effect of endurance training on skeletal muscle phospholipid molecular species from high-fat fed rats. Twelve female Sprague-Dawley rats were fed a high-fat diet (78.1% energy). The rats were randomly divided into two groups, a sedentary control group and a trained group (125 min of treadmill running at 8 m/min, 4 days/wk for 4 weeks). Forty-eight hours after their last training bout phospholipids were extracted from the red and white vastus lateralis and analyzed by electrospray-ionization mass spectrometry. Exercise training was associated with significant alterations in the relative abundance of a number of phospholipid molecular species. These changes were more prominent in red vastus lateralis than white vastus lateralis. The largest observed change was an increase of similar to 30% in the abundance of 1-palmitoyl-2-linoleoyl phosphatidylcholine ions in oxidative fibers. Reductions in the relative abundance of a number of phospholipids containing long-chain n-3 polyunsaturated fatty acids were also observed. These data suggest a possible reduction in phospholipid remodeling in the trained animals. This results in a decrease in the phospholipid n-3 to n-6 ratio that may in turn influence endurance capacity.

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We have determined the effect of two exercise-training intensities on the phospholipid profile of both glycolytic and oxidative muscle fibers of female Sprague-Dawley rats using electrospray-ionization mass spectrometry. Animals were randomly divided into three training groups: control, which performed no exercise training; low-intensity (8 m/min) treadmill running; or high-intensity (28 m/min) treadmill running. All exercise-trained rats ran 1,000 m/session for 4 days/wk for 4 wk and were killed 48 h after the last training bout. Exercise training was found to produce no novel phospholipid species but was associated with significant alterations in the relative abundance of a number of phospholipid molecular species. These changes were more prominent in glycolytic (white vastus lateralis) than in oxidative (red vastus lateralis) muscle fibers. The largest observed change was a decrease of ∼20% in the abundance of 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine [PE(18:0/22:6); P < 0.001] ions in both the low- and high-intensity training regimes in glycolytic fibers. Increases in the abundance of 1-oleoyl-2-linoleoyl phopshatidic acid [PA(18:1/18:2); P < 0.001] and 1-alkenylpalmitoyl-2-linoleoyl phosphatidylethanolamine [plasmenyl PE (16:0/18:2); P < 0.005] ions were also observed for both training regimes in glycolytic fibers. We conclude that exercise training results in a remodeling of phospholipids in rat skeletal muscle. Even though little is known about the physiological or pathophysiological role of specific phospholipid molecular species in skeletal muscle, it is likely that this remodeling will have an impact on a range of cellular functions.

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Background Hamstring strain injuries (HSIs) are the most common injury type in Australian football and the rate of recurrence has been consistently high for a number of years. Long lasting neuromuscular inhibition has been noted in previously injured athletes but it is not known if this influences athletes adaptive response to training. Purpose To determine if elite Australian footballers with a prior unilateral HSI (previously injured group) display lesser improvements in eccentric hamstring strength during pre-season training compared to athletes without a history of HSI (control group). Study design Prospective cohort study. Methods Ninety-nine elite Australian footballers participated (17 with a history of unilateral HSI in the previous 12 month period). Eccentric hamstring strength was assessed at the start and end of pre-season training using an instrumented Nordic hamstring device. Change in eccentric strength across preseason was determine in absolute terms and normalised to start of preseason strength. Start of preseason strength was used as a covariate to control for differences in starting strength. Results The left and right limbs in the control group showed no difference in absolute or relative change (left limb absolute change, 60.7±72.9N; relative change, 1.28±0.34; right limb absolute change, 48.6±83.8N; relative change, 1.24±0.43) . Similarly, the injured and uninjured limbs from the previously injured group showed no difference for either absolute or relative measures of change (injured limb absolute change, 13.1±57.7N; relative change, 1.07±0.18; uninjured limb absolute change, 14.7±54.0N; relative change, 1.07±0.22N). The previously injured group displayed a significantly lesser increase in eccentric hamstring strength across the preseason (absolute change, 13.9±55.0; relative change, 1.07±0.20) compared to the control group (absolute change, 54.6±78.5; relative change, 1.26±0.39) for both absolute and relative measures (p < 0.001), even after controlling for differences in start of pre-season eccentric hamstring strength, which had a significant effect on strength improvement. Conclusion Elite Australian footballers with a unilateral HSI history displayed lesser improvements in eccentric hamstring strength across preseason training. The smaller improvements were not restricted to the previously injured limb as the contralateral limb also displayed similarly small improvements in eccentric strength. Whether this is the cause of or the result of injury remains to be seen, but it has the potential to contribute to the risk of hamstring strain re-injury.

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We investigated the effect of cold water immersion (CWI) on the recovery of muscle function and physiological responses following high-intensity resistance exercise. Using a randomized, cross-over design, 10 physically active men performed high-intensity resistance exercise, followed by one of two recovery interventions: 10 min of cold water immersion at 10°C, or 10 min active recovery (low-intensity cycling). After the recovery interventions, maximal muscle function was assessed after 2 h and 4 h by measuring jump height and isometric squat strength. Submaximal muscle function was assessed after 6 h by measuring the average load lifted during six sets of 10 squats at 80% 1RM. Intramuscular temperature (1 cm) was also recorded, and venous blood samples were analyzed for markers of metabolism, vasoconstriction and muscle damage. CWI did not enhance recovery of maximal muscle function. However, during the final three sets of the submaximal muscle function test, the participants lifted a greater load (p<0.05; 38%; Cohen’s d 1.3) following CWI compared with active recovery. During CWI, muscle temperature decreased 6°C below post-exercise values, and remained below pre-exercise values for another 35 min. Venous blood O2 saturation decreased below pre-exercise values for 1.5 h after CWI. Serum endothelin-1 concentration did not change after CWI, whereas it decreased after active recovery. Plasma myoglobin concentration was lower, whereas plasma interleukin-6 concentration was higher after CWI compared with active recovery. These results suggest that cold water immersion after resistance exercise allow athletes to complete more work during subsequent training sessions, which could enhance long-term training adaptations.

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Researchers have postulated that reduced hip-abductor muscle strength may have a role in the progression of knee osteoarthritis by increasing the external knee-adduction moment. However, the relationship between hip-abductor strength and frontal-plane biomechanics remains unclear. To experimentally reduce hip-abduction strength and observe the subsequent changes in frontal-plane biomechanics. Descriptive laboratory study. Research laboratory. Eight healthy, recreationally active men (age = 27 ± 6 years, height = 1.75 ± 0.11 m, mass = 76.1 ± 10.0 kg). All participants underwent a superior gluteal nerve block injection to reduce the force output of the hip-abductor muscle group. Maximal isometric hip-abduction strength and gait biomechanical data were collected before and after the injections. Gait biomechanical variables collected during walking consisted of knee- and hip-adduction moments and impulses and the peak angles of contralateral pelvic drop, hip adduction, and ipsilateral trunk lean. Hip-abduction strength was reduced after the injection (P = .001) and remained lower than baseline values at the completion of the postinjection gait data collection (P = .02). No alterations in hip- or knee-adduction moments (hip: P = .11; knee: P = .52) or impulses (hip: P = .16; knee: P = .41) were found after the nerve block. Similarly, no changes in angular kinematics were observed for contralateral pelvic drop (P = .53), ipsilateral trunk lean (P = .78), or hip adduction (P = .48). A short-term reduction in hip-abductor strength was not associated with alterations in the frontal-plane gait biomechanics of young, healthy men. Further research is needed to determine whether a similar relationship is true in older adults with knee osteoarthritis.

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Objective The aim of this systematic review and meta-analysis was to determine the overall effect of resistance training (RT) on measures of muscular strength in people with Parkinson’s disease (PD). Methods Controlled trials with parallel-group-design were identified from computerized literature searching and citation tracking performed until August 2014. Two reviewers independently screened for eligibility and assessed the quality of the studies using the Cochrane risk-of-bias-tool. For each study, mean differences (MD) or standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for continuous outcomes based on between-group comparisons using post-intervention data. Subgroup analysis was conducted based on differences in study design. Results Nine studies met the inclusion criteria; all had a moderate to high risk of bias. Pooled data showed that knee extension, knee flexion and leg press strength were significantly greater in PD patients who undertook RT compared to control groups with or without interventions. Subgroups were: RT vs. control-without-intervention, RT vs. control-with-intervention, RT-with-other-form-of-exercise vs. control-without-intervention, RT-with-other-form-of-exercise vs. control-with-intervention. Pooled subgroup analysis showed that RT combined with aerobic/balance/stretching exercise resulted in significantly greater knee extension, knee flexion and leg press strength compared with no-intervention. Compared to treadmill or balance exercise it resulted in greater knee flexion, but not knee extension or leg press strength. RT alone resulted in greater knee extension and flexion strength compared to stretching, but not in greater leg press strength compared to no-intervention. Discussion Overall, the current evidence suggests that exercise interventions that contain RT may be effective in improving muscular strength in people with PD compared with no exercise. However, depending on muscle group and/or training dose, RT may not be superior to other exercise types. Interventions which combine RT with other exercise may be most effective. Findings should be interpreted with caution due to the relatively high risk of bias of most studies.