Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial.

Testosterone acts directly at androgen receptors and also exerts potent actions following 5α-reduction to dihydrotestosterone (DHT). Finasteride (type II 5α-reductase inhibitor) lowers DHT and is used to treat benign prostatic hyperplasia. However, it is unknown whether elevated DHT mediates either beneficial musculoskeletal effects or prostate enlargement resulting from higher-than-replacement doses of testosterone. Our purpose was to determine whether administration of testosterone plus finasteride to older hypogonadal men could produce musculoskeletal benefits without prostate enlargement. Sixty men aged ≥60 yr with a serum testosterone concentration of ≤300 ng/dl or bioavailable testosterone ≤70 ng/dl received 52 wk of treatment with testosterone enanthate (TE; 125 mg/wk) vs. vehicle, paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased upper and lower body muscle strength by 8-14% (P = 0.015 to <0.001), fat-free mass 4.04 kg (P = 0.032), lumbar spine bone mineral density (BMD) 4.19% (P < 0.001), and total hip BMD 1.96% (P = 0.024) while reducing total body fat -3.87 kg (P < 0.001) and trunk fat -1.88 kg (P = 0.0051). In the first 3 mo, testosterone increased hematocrit 4.13% (P < 0.001). Coadministration of finasteride did not alter any of these effects. Over 12 mo, testosterone also increased prostate volume 11.4 cm(3) (P = 0.0051), an effect that was completely prevented by finasteride (P = 0.0027). We conclude that a higher-than-replacement TE combined with finasteride significantly increases muscle strength and BMD and reduces body fat without causing prostate enlargement. These results demonstrate that elevated DHT mediates testosterone-induced prostate enlargement but is not required for benefits in musculoskeletal or adipose tissue.

17ß-Hydroxyestra-4,9,11-trien-3-one (trenbolone) exhibits tissue selective anabolic activity: effects on muscle, bone, adiposity, hemoglobin, and prostate.

Selective androgen receptor modulators (SARMs) now under development can protect against muscle and bone loss without causing prostate growth or polycythemia. 17ß-Hydroxyestra-4,9,11-trien-3-one (trenbolone), a potent testosterone analog, may have SARM-like actions because, unlike testosterone, trenbolone does not undergo tissue-specific 5α-reduction to form more potent androgens. We tested the hypothesis that trenbolone-enanthate (TREN) might prevent orchiectomy-induced losses in muscle and bone and visceral fat accumulation without increasing prostate mass or resulting in adverse hemoglobin elevations. Male F344 rats aged 3 mo underwent orchiectomy or remained intact and were administered graded doses of TREN, supraphysiological testosterone-enanthate, or vehicle for 29 days. In both intact and orchiectomized animals, all TREN doses and supraphysiological testosterone-enanthate augmented androgen-sensitive levator ani/bulbocavernosus muscle mass by 35-40% above shams (P ≤ 0.001) and produced a dose-dependent partial protection against orchiectomy-induced total and trabecular bone mineral density losses (P < 0.05) and visceral fat accumulation (P < 0.05). The lowest doses of TREN successfully maintained prostate mass and hemoglobin concentrations at sham levels in both intact and orchiectomized animals, whereas supraphysiological testosterone-enanthate and high-dose TREN elevated prostate mass by 84 and 68%, respectively (P < 0.01). In summary, low-dose administration of the non-5α-reducible androgen TREN maintains prostate mass and hemoglobin concentrations near the level of shams while producing potent myotrophic actions in skeletal muscle and partial protection against orchiectomy-induced bone loss and visceral fat accumulation. Our findings indicate that TREN has advantages over supraphysiological testosterone and supports the need for future preclinical studies examining the viability of TREN as an option for androgen replacement therapy.

Growth hormone isoform responses to GABA ingestion at rest and after exercise.

UNLABELLED: Oral administration of the amino acid/inhibitory neurotransmitter gamma aminobutyric acid (GABA) reportedly elevates resting serum growth hormone (GH) concentrations. PURPOSE: To test the hypothesis that GABA ingestion stimulates immunoreactive GH (irGH) and immunofunctional GH (ifGH) release at rest and that GABA augments the resistance exercise-induced irGH/ifGH responses. METHODS: Eleven resistance-trained men (18-30 yr) participated in this randomized, double-blind, placebo-controlled, crossover study. During each experimental bout, participants ingested either 3 g of GABA or sucrose placebo (P), followed either by resting or resistance exercise sessions. Fasting venous blood samples were acquired immediately before and at 15, 30, 45, 60, 75, and 90 min after GABA or P ingestion and were assayed for irGH and ifGH. RESULTS: At rest, GABA ingestion elevated both irGH and ifGH compared with placebo. Specifically, peak concentrations of both hormones were elevated by about 400%, and the area under the curve (AUC) was elevated by about 375% (P < 0.05). Resistance exercise (EX-P) elevated time-point (15-60 min) irGH and ifGH concentrations compared with rest (P < 0.05). The combination of GABA and resistance exercise (EX-GABA) also elevated the peak, AUC, and the 15- to 60-min time-point irGH and ifGH responses compared with resting conditions (P < 0.05). Additionally, 200% greater irGH (P < 0.01) and 175% greater ifGH (P < 0.05) concentrations were observed in the EX-GABA than in the EX-P condition, 30 min after ingestion. GABA ingestion did not alter the irGH to ifGH ratio, and, under all conditions, ifGH represented approximately 50% of irGH. CONCLUSIONS: Our data indicate that ingested GABA elevates resting and postexercise irGH and ifGH concentrations. The extent to which irGH/ifGH secretion contributes to skeletal muscle hypertrophy is unknown, although augmenting the postexercise irGH/ifGH response may improve resistance training-induced muscular adaptations.

Cardiovascular/non-insulin-dependent diabetes mellitus risk factors and intramyocellular lipid in healthy subjects: a sex comparison.

Little is known about the relationship between intramyocellular lipid (IMCL) and coronary artery disease (CAD)/non-insulin-dependent diabetes mellitus risk factors. The aim of the study was to examine the relationship between IMCL and CAD/non-insulin-dependent diabetes mellitus risk factors in healthy male (n = 9) and female (n = 10) subjects with similar norm-based aerobic fitness and body composition. Nineteen volunteers (21-36 years) completed health and physical activity questionnaires, cardiovascular and body composition evaluation, and assessment of thigh IMCL using proton magnetic resonance spectroscopy. Outcome measures were blood pressure, total cholesterol, high-density lipoprotein cholesterol, C-reactive protein, interleukin 6, tumor necrosis factor alpha (TNF-alpha), homocysteine, insulin resistance (IR), percentage of body fat, waist-to-hip ratio, physical activity levels, and cardiovascular fitness. Analysis of variance was used for group comparisons. Correlation analyses were used to determine association between variables, and stepwise regression was used to determine predictive variables of IR. Women had 2-fold higher IMCL and greater IR than men (P < .05). Men had greater plasma homocysteine and interleukin 6 concentration (P < .05) as well as stronger correlations with CAD risk factors than female subjects. Correlation analyses using all subjects revealed a significant relationship between IMCL and waist-to-hip ratio, body weight, percentage of body fat, and IR. In the regression analysis, age, IMCL, and TNF-alpha were the strongest predictors of IR (R2 = 0.62, P < .01). Our results suggest that female subjects, matched for age and fitness, have higher IMCL compared with their male counterparts. IMCL was correlated with several CAD and prediabetes markers in both male and female subjects. In the final regression model, age, IMCL, and TNF-alpha were the strongest predictors of IR. Future studies with larger sample sizes are warranted.

Review of health risks of low testosterone and testosterone administration.

Hypogonadism is prevalent in older men and testosterone replacement therapy (TRT) for older hypogonadal men is a promising therapy. However, a number of important clinical concerns over TRT safety remain unsolved due to a lack of large-scale randomized clinical trials directly comparing the health risks of untreated hypogonadism vs long-term use of TRT. Meta-analyses of clinical trials of TRT as of 2010 have identified three major adverse events resulting from TRT: polycythemia, an increase in prostate-related events, and a slight reduction in serum high-density lipoprotein cholesterol. There are other purported health risks but their incidence can be neither confirmed nor denied based on the small number of subjects that have been studied to date. Furthermore, subsequent literature is equivocal with regard to the safety and utility of TRT and this topic has been subject to contentious debate. Since January 2014, the United States Food and Drug Administration has released two official announcements regarding the safety of TRT and clinical monitoring the risks in TRT users. Additionally, the health risks related to the clinical presentation of low or declining testosterone levels not been resolved in the current literature. Because TRT is prescribed in the context of putative risks resulting from reduced testosterone levels, we reviewed the epidemiology and reported risks of low testosterone levels. We also highlight the current information about TRT utilization, the risks most often claimed to be associated with TRT, and current or emerging alternatives to TRT.

Intramyocellular lipid changes in men and women during aerobic exercise: a (1)H-magnetic resonance spectroscopy study.

This study was designed to compare intramyocellular lipid (IMCL) changes during 60 min of submaximal exercise in men and women. Eighteen moderately active (18-38 yr) men (n = 9) and women (n = 9) were recruited. Maximum oxygen consumption (O(2)max) and body composition were used to match subjects for aerobic fitness and body composition. Subjects performed cycle ergometry for 1 h at 65% of O(2)max. Expired gases were collected throughout exercise to determine caloric expenditure and substrate use. Blood samples were collected before and after exercise to evaluate markers of lipid metabolism. Pre- and postexercise proton spectra were acquired from the vastus lateralis using a 3-T whole-body imaging system. Spectra were acquired from an 18-mm(3) region of interest (echo time = 45 msec; repetition time = 2000 msec) for IMCL evaluation. IMCL decreased significantly with exercise (11.5-28.5% for men and 17.1-21.7% for women) (P < 0.05); however, there were no significant differences between men and women. Although changes were found for many plasma variables [free fatty acids, glycerol, and norepinephrine (P < 0.05)], group differences were only evident for norepinephrine. In conclusion, a significant decrease in IMCL was observed during 60 min of cycling in matched men and women.

Transcriptional regulation of myotrophic actions by testosterone and trenbolone on androgen-responsive muscle.

Androgens regulate body composition and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. Recently, we demonstrated that trenbolone (a potent synthetic testosterone analogue that is not a substrate for 5-alpha reductase or for aromatase) induces myotrophic effects in skeletal muscle without causing prostate enlargement, which is in contrast to the known prostate enlarging effects of testosterone. These previous results suggest that the 5α-reduction of testosterone is not required for myotrophic action. We now report differential gene expression in response to testosterone versus trenbolone in the highly androgen-sensitive levator ani/bulbocavernosus (LABC) muscle complex of the adult rat after 6weeks of orchiectomy (ORX), using real time PCR. The ORX-induced expression of atrogenes (Muscle RING-finger protein-1 [MuRF1] and atrogin-1) was suppressed by both androgens, with trenbolone producing a greater suppression of atrogin-1 mRNA compared to testosterone. Both androgens elevated expression of anabolic genes (insulin-like growth factor-1 and mechano-growth factor) after ORX. ORX-induced increases in expression of glucocorticoid receptor (GR) mRNA were suppressed by trenbolone treatment, but not testosterone. In ORX animals, testosterone promoted WNT1-inducible-signaling pathway protein 2 (WISP-2) gene expression while trenbolone did not. Testosterone and trenbolone equally enhanced muscle regeneration as shown by increases in LABC mass and in protein expression of embryonic myosin by western blotting. In addition, testosterone increased WISP-2 protein levels. Together, these findings identify specific mechanisms by which testosterone and trenbolone may regulate skeletal muscle maintenance and growth.

Intracrine and myotrophic roles of 5α-reductase and androgens: a review.

UNLABELLED: Historically, the circulation was thought to be the primary source of androgens influencing skeletal muscle. However, a growing body of research indicates that skeletal muscle expresses several androgen-synthesizing enzymes, including 5α-reductase. The intramuscular expression of these enzymes suggests that skeletal muscle is capable of synthesizing bioactive androgens, which could induce myotrophic effects via intracrine action. PURPOSE: The aim of this brief review is to discuss recent research related to the intracrine and myotrophic roles of androgens, with particular focus on 5α-reductase as a myotrophic mediator. METHODS: Included in the review are 17 reviews and 58 original studies that were identified by a systematic review from MEDLINE and deemed particularly relevant to our purpose. Results are summarized to provide an overview of 5α-reductase as a mediator of the myotrophic effects of androgens. In particular, discussions are included regarding androgen biosynthesis and androgen signaling within skeletal muscle, the effects of exercise on intramuscular androgen biosynthesis, and clinical applications of androgens and of a new class of myotrophic agonists termed selective androgen receptor modulator. RESULTS: The ability of several peripheral tissues to synthesize bioactive androgens is well documented in the literature. Herein, we summarize newer studies that demonstrate that 1) skeletal muscle has the capability to synthesize both testosterone and dihydrotestosterone from dehydroepiandrosterone, which is present in abundance within the circulation, and 2) that exercise increases the expression of certain androgen-biosynthesizing enzymes within muscle. CONCLUSIONS: Intramuscularly synthesized androgens have the potential to influence skeletal muscle via intracrine action; however, their exact role in skeletal muscle development and maintenance requires further elucidation.

Influence of androgens on circulating adiponectin in male and female rodents.

Several endocrine factors, including sex-steroid hormones are known to influence adiponectin secretion. Our purpose was to evaluate the influence of testosterone and of the synthetic non-aromatizable/non-5α reducible androgen 17ß-hydroxyestra-4,9,11-trien-3-one (trenbolone) on circulating adiponectin and adiponectin protein expression within visceral fat. Young male and female F344 rats underwent sham surgery (SHAM), gonadectomy (GX), or GX plus supraphysiologic testosterone-enanthate (TE) administration. Total circulating adiponectin was 39% higher in intact SHAM females than SHAM males (p<0.05). GX increased total adiponectin by 29-34% in both sexes (p<0.05), while TE reduced adiponectin to concentrations that were 46-53% below respective SHAMs (p≤0.001) and ablated the difference in adiponectin between sexes. No differences in high molecular weight (HMW) adiponectin were observed between sexes or treatments. Adiponectin concentrations were highly and negatively associated with serum testosterone (males: r = -0.746 and females: r = -0.742, p≤0.001); however, no association was present between adiponectin and estradiol. In separate experiments, trenbolone-enanthate (TREN) prevented the GX-induced increase in serum adiponectin (p≤0.001) in young animals, with Low-dose TREN restoring adiponectin to the level of SHAMs and higher doses of TREN reducing adiponectin to below SHAM concentrations (p≤0.001). Similarly, TREN reduced adiponectin protein expression within visceral fat (p<0.05). In adult GX males, Low-dose TREN also reduced total adiponectin and visceral fat mass to a similar magnitude as TE, while increasing serum HMW adiponectin above SHAM and GX animals (p<0.05). Serum adiponectin was positively associated with visceral fat mass in young (r = 0.596, p≤0.001) and adult animals (r = 0.657, p≤0.001). Our results indicate that androgens reduce circulating total adiponectin concentrations in a dose-dependent manner, while maintaining HMW adiponectin. This change is directionally similar to the androgen-induced lipolytic effects on visceral adiposity and equal in magnitude between TE and TREN, suggesting that neither the aromatization nor the 5α reduction of androgens is required for this effect.

A rehabilitation exercise program induces severe bone mineral deficits in estrogen-deficient rats after extended disuse.

OBJECTIVE: Both estrogen and mechanical loading regulate bone maintenance. However, mechanical overload seems less effective in enhancing bone mineral density (BMD) in estrogen-deficient women. The aim of this study was to determine whether estradiol (E2) influences early-phase bone adaptations to reambulation (REAMB) and/or rehabilitation exercises after hindlimb unloading (HLU) of ovariectomized rats. METHODS: Eighty-one 5-month-old female Sprague-Dawley rats were randomized into the following groups: (1) intact controls, (2) ovariectomy (OVX), (3) OVX + E2, (4) OVX + 4 weeks of HLU, (5) OVX + E2 + HLU, (6) OVX + HLU + 2 weeks of quadrupedal REAMB, (7) OVX + E2 + HLU + REAMB, (8) OVX + HLU + REAMB + supplemental climbing, jumping, and balance exercises (EX), or (9) OVX + E2 + HLU + REAMB + EX. Serial dual-energy x-ray absorptiometry scans were performed to track total body bone characteristics throughout the study, and peripheral quantitative computerized tomography was used to determine distal femoral metaphyseal bone mineral characteristics. RESULTS: Total body BMD increased by 4% to 8% in all animals receiving supplemental E2, whereas BMD did not change in animals without E2. OVX reduced trabecular BMD at the femoral metaphysis, and HLU exacerbated this loss while also reducing cortical BMD. E2 protected against OVX + HLU-induced bone loss at the femoral metaphysis. Conversely, REAMB did not alter BMD, regardless of estrogen status. In the absence of E2, REAMB + EX resulted in severe bone loss after OVX + HLU, with trabecular BMD and cortical BMD measurements that were 91% and 7% below those of controls, respectively (P ≤ 0.001). However, in the presence of E2, REAMB + EX did not negatively influence bone mineral characteristics. CONCLUSIONS: E2 protects against bone loss resulting from combined OVX + HLU of rodents. In the absence of estrogen, exercise induces disadvantageous early-phase bone adaptations after extended disuse.

17ß-Hydroxyestra-4,9,11-trien-3-one (Trenbolone) preserves bone mineral density in skeletally mature orchiectomized rats without prostate enlargement.

Testosterone enanthate (TE) administration attenuates bone loss in orchiectomized (ORX) rats. However, testosterone administration may increase risk for prostate/lower urinary tract related adverse events and polycythemia in humans. Trenbolone enanthate (TREN) is a synthetic testosterone analogue that preserves bone mineral density (BMD) and results in less prostate enlargement than testosterone in young ORX rodents. The purpose of this experiment was to determine if intramuscular TREN administration attenuates bone loss and maintains bone strength, without increasing prostate mass or hemoglobin concentrations in skeletally mature ORX rodents. Forty, 10 month old male F344/Brown Norway rats were randomized into SHAM, ORX, ORX+TE (7.0mg/week), and ORX+TREN (1.0mg/week) groups. Following surgery, animals recovered for 1 week and then received weekly: vehicle, TE, or TREN intramuscularly for 5 weeks. ORX reduced total and trabecular (t) BMD at the distal femoral metaphysis compared with SHAMs, while both TREN and TE completely prevented these reductions. TREN treatment also increased femoral neck strength by 28% compared with ORX animals (p<0.05), while TE did not alter femoral neck strength. In addition, TE nearly doubled prostate mass, compared with SHAMs (p<0.05). Conversely, TREN induced a non-significant 20% reduction in prostate mass compared with SHAMs, ultimately producing a prostate mass that was 64% below that found in ORX+TE animals (p<0.01). Hemoglobin concentrations and levator ani/bulbocavernosus (LABC) muscle mass were elevated in ORX+TE and ORX+TREN animals to a similar degree above both SHAM and ORX conditions (p<0.01). In skeletally mature rodents, both high-dose TE and low-dose TREN completely prevented the ORX-induced loss of tBMD at the distal femoral metaphysis and increased LABC mass. TREN also augmented femoral neck strength and maintained prostate mass at SHAM levels. These findings indicate that TREN may be an advantageous agent for future clinical trials evaluating agents capable of preventing bone loss resulting from androgen deficiency.

Tissue selectivity and potential clinical applications of trenbolone (17beta-hydroxyestra-4,9,11-trien-3-one): A potent anabolic steroid with reduced androgenic and estrogenic activity.

Recently, the development of selective androgen receptor modulators (SARMs) has been suggested as a means of combating the deleterious catabolic effects of hypogonadism, especially in skeletal muscle and bone, without inducing the undesirable androgenic effects (e.g., prostate enlargement and polycythemia) associated with testosterone administration. 17beta-Hydroxyestra-4,9,11-trien-3-one (trenbolone; 17beta-TBOH), a synthetic analog of testosterone, may be capable of inducing SARM-like effects as it binds to androgen receptors (ARs) with approximately three times the affinity of testosterone and has been shown to augment skeletal muscle mass and bone growth and reduce adiposity in a variety of mammalian species. In addition to its direct actions through ARs, 17beta-TBOH may also exert anabolic effects by altering the action of endogenous growth factors or inhibiting the action of glucocorticoids. Compared to testosterone, 17beta-TBOH appears to induce less growth in androgen-sensitive organs which highly express the 5alpha reductase enzyme (e.g., prostate tissue and accessory sex organs). The reduced androgenic effects result from the fact that 17beta-TBOH is metabolized to less potent androgens in vivo; while testosterone undergoes tissue-specific biotransformation to more potent steroids, dihydrotestosterone and 17beta-estradiol, via the 5alpha-reductase and aromatase enzymes, respectively. Thus the metabolism of 17beta-TBOH provides a basis for future research evaluating its safety and efficacy as a means of combating muscle and bone wasting conditions, obesity, and/or androgen insensitivity syndromes in humans, similar to that of other SARMs which are currently in development.

Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF).

Brain derived neurotrophic factor (BDNF) is postulated to be an important mediator of exercise-induced neuroprotection. We tested the hypothesis that resistance exercise elevates circulating BDNF. Twenty healthy untrained college-aged males underwent a 5-week traditional or eccentric-enhanced progressive resistance training intervention. Blood was acquired at rest and 1, 30, and 60min following a standardized resistance exercise testing bout performed at baseline and at the completion of the intervention. Serum BDNF responses did not differ between the two groups at any time point during baseline or post-intervention testing; thus, all values were combined into a single cohort for further analysis. Resting BDNF was not altered by the exercise training intervention [23,304+/-1835pg/ml (baseline) vs. 19,433+/-1992pg/ml (post-intervention)]. Following the baseline resistance exercise bout, serum BDNF increased 32% (p<0.05) and was gradually reduced to 41% below resting levels at 60min into recovery (p<0.01). During post-intervention testing, serum BDNF increased 77% in response to the standardized resistance exercise bout (p<0.01) and returned to resting values within 30min. Ultimately, the change in serum BDNF from rest to immediately post-exercise was 98% greater at post-intervention than at baseline (p<0.05). Our study is the first to demonstrate that resistance exercise induces a robust, yet transient, elevation of circulating BDNF and that progressive resistance training augments this response; perhaps demonstrating one mechanism through which exercise influences brain health.

Increased caloric intake soon after exercise in cold water.

We examined the acute effect of cold-water temperature on post-exercise energy intake (EI) for 1 h. In a randomized, crossover design, 11 men (25.6 +/- 5 y) exercised for 45 min on a submersed cycle ergometer at 60 +/- 2% VO2max in 33 degrees C (neutral) and 20 degrees (cold) water temperatures, and also rested for 45 min (control). Energy expenditure (EE) was determined using indirect calorimetry before, during, and after each condition. Following exercise or rest, subjects had free access to a standard assortment of food items of known caloric value. EE was similar for the cold and neutral water conditions, averaging 505 +/- 22 (+/- standard deviation) and 517 +/- 42 kcal, respectively (P = NS). EI after the cold condition averaged 877 +/- 457 kcal, 44% and 41% higher (P < 0.05) than for the neutral and resting conditions, respectively. Cold-water temperature thus stimulated post-exercise EI. Water temperature warrants consideration in aquatic programs designed for weight loss.

Resistance training improves gait kinematics in persons with multiple sclerosis.

OBJECTIVE: To evaluate the effects of an 8-week lower-body resistance-training program on walking mechanics in persons with multiple sclerosis (MS). DESIGN: Repeated-measures design, evaluating gait kinematics before and after an 8-week progressive resistance-training intervention. SETTING: Biomechanics laboratory and fitness center (with conventional, commercially available resistance-training equipment). PARTICIPANTS: Eight ambulatory subjects with MS (age, 46.0+/-11.5 y) with Expanded Disability Status Scale scores ranging from 2.5 to 5.5. INTERVENTION: An 8-week progressive resistance-training program. MAIN OUTCOME MEASURES: Kinematic gait parameters including knee range of motion, duration of stance, swing, and double-support phases in seconds and as percentages of the stride time, percentage of stride time spent in stance, swing, and double-support phases, step length, foot angle, stride length, velocity, step width, and toe clearance for both the more affected and less affected lower limbs. Isometric strength, 3-minute stepping, fatigue, and self-reported disability were also measured. RESULTS: After 2 months of resistance training, there were significant increases (P<.05) in percentage of stride time in the swing phase, step length, stride length, and foot angle; and significant decreases (P<.05) in percentage of stride time in the stance and double-support phases, duration of the double-support phase, and toe clearance. Isometric leg strength improved (P<.05) in 2 of the 4 muscle groups tested. Fatigue indices decreased (P=.04), whereas self-reported disability tended to decrease (P=.07) following the training program. Three-minute stepping increased by 8.7%. CONCLUSIONS: Resistance training may be an effective intervention strategy for improving walking and functional ability in moderately disabled persons with MS.