Soluble activin receptor type IIB decoy receptor differentially impacts murine osteogenesis imperfecta muscle function.

INTRODUCTION: Osteogenesis imperfecta (OI) is characterized by skeletal fragility and muscle weakness. In this study we investigated the effects of soluble activin type IIB receptor (sActRIIB-mFc) on muscle mass and function in 2 distinct mouse models of OI: osteogenesis imperfecta murine (oim) and +/G610C. METHODS: Wild-type (WT), +/G610C, and oim/oim mice were treated from 2 to 4 months of age with Tris-buffered saline (vehicle) or sActRIIB-mFc and their hindlimb muscles evaluated for mass, morphology, and contractile function. RESULTS: sActRIIB-mFc-treated WT, +/G610C, and oim/oim mice had increased hindlimb muscle weights and myofiber cross-sectional area compared with vehicle-treated counterparts. sActRIIB-mFc-treated oim/oim mice also exhibited increased contractile function relative to vehicle-treated counterparts. DISCUSSION: Blocking endogenous ActRIIB was effective at increasing muscle size in mouse models of OI, and increasing contractile function in oim/oim mice. ActRIIB inhibitors may provide a potential mutation-specific therapeutic option for compromised muscle function in OI. Muscle Nerve 57: 294-304, 2018.

Physical Activity Intervention Effects on Physical Function Among Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis.

The purpose of this systematic review and meta-analysis was to determine the effects of supervised resistance and/or aerobic training physical activity interventions on performance-based measures of physical functioning among community-dwelling older adults, and to identify factors impacting intervention effectiveness. Diverse search strategies were used to identify eligible studies. Standardized mean difference effect sizes (d, ES) were synthesized using a random effects model. Moderator analyses were conducted using subgroup analyses and meta-regression. Twenty-eight studies were included. Moderator analyses were limited by inconsistent reporting of sample and intervention characteristics. The overall mean ES was 0.45 (k = 38, p ≤ .01), representing a clinically meaningful reduction of 0.92 s in the Timed Up and Go for treatment versus control. More minutes per week (p < .01) and longer intervention session duration (p < .01) were associated with larger effects. Interventions were especially effective among frail participants (d = 1.09). Future research should clearly describe sample and intervention characteristics and incorporate frail populations.

Phenotypic and molecular differences between rats selectively bred to voluntarily run high vs. low nightly distances.

The purpose of the present study was to partially phenotype male and female rats from generations 8-10 (G8-G10) that had been selectively bred to possess low (LVR) vs. high voluntary running (HVR) behavior. Over the first 6 days with wheels, 34-day-old G8 male and female LVRs ran shorter distances (P < 0.001), spent less time running (P < 0.001), and ran slower (P < 0.001) than their G8 male and female HVR counterparts, respectively. HVR and LVR lines consumed similar amounts of standard chow with or without wheels. No inherent difference existed in PGC-1α mRNA in the plantaris and soleus muscles of LVR and HVR nonrunners, although G8 LVR rats inherently possessed less NADH-positive superficial plantaris fibers compared with G8 HVR rats. While day 28 body mass tended to be greater in both sexes of G9-G10 LVR nonrunners vs. G9-G10 HVR nonrunners (P = 0.06), body fat percentage was similar between lines. G9-G10 HVRs had fat mass loss after 6 days of running compared with their prerunning values, while LVR did not lose or gain fat mass during the 6-day voluntary running period. RNA deep sequencing efforts in the nucleus accumbens showed only eight transcripts to be >1.5-fold differentially expressed between lines in HVR and LVR nonrunners. Interestingly, HVRs presented less Oprd1 mRNA, which ties in to potential differences in dopaminergic signaling between lines. This unique animal model provides further evidence as to how exercise may be mechanistically regulated.

Sex hormones differentially influence voluntary running activity, food intake and body weight in aging female and male rats.

The aim of this study was to examine the longer-term effects of reduced gonadal hormones on food intake, food efficiency, voluntary running activity and body weight in mature male and female rats, compared to age-matched controls. We hypothesized that hormonal effects would differ for rats that were not rapidly growing and our results are consistent with this hypothesis. 6-8 month male and female rats were divided into four groups: Female and male control groups and a female and male experimental group. Control groups were intact for 46 weeks. Experimental groups were intact during Phase I (16 weeks), ovariectomized or orchidectomized during Phase II (20 weeks), and received estrogen or testosterone hormone replacement therapy (HRT) during the final Phase III (10 weeks). Food intake and running distance were monitored daily and body weight was recorded weekly for 46 weeks. Contrary to findings for young and growing animals, we did not observe a (1) stabilization of food intake in female rats following OVX, (2) loss of body weight with ORX in males, or (3) complete restoration of running activity in ORX males given testosterone, compared to females given estrogen. Feeding efficiency was not affected by aging in females or males. Loss of estrogen increased energy intake whereas reduced testosterone in males resulted in a negative energy balance. Findings suggest variable hormonal effects for aging male/female rats.

A rehabilitation exercise program to remediate skeletal muscle atrophy in an estrogen-deficient organism may be ineffective.

To determine rehabilitation exercise program effects under hormone deficient (ovariectomy or OVX) and hormone supplemented [OVX + 17-beta estradiol (E2)] conditions. Mature female rats (n = 123) were assigned to OVX or OVX + E2-supplemented groups. OVX and OVX + E2 groups were allocated to one of four conditions: (1) control, (2) hindlimb unweighted (HLU) for 4 weeks to induce muscle atrophy, (3) cage Recovery for 2 weeks after HLU, and (4) Recovery with 2 weeks of rehabilitation exercise program after 4 weeks of HLU. Atrophy following HLU was comparable for OVX and OVX + E2-supplemented rats and was significant in all muscles examined (soleus, tibialis anterior, plantaris, gastrocnemius, quadriceps). Also significant with HLU was the decline in muscle force (P < 0.05) in soleus, plantaris, gastrocnemius and tibialis anterior (quadriceps not tested). There were trends toward return of muscle mass in Recovery OVX and Recovery OVX + E2 groups but only the E2 supplemented OVX rats had return of muscle mass (4/5 muscles studied) with exercise. Peak tetanic tension (Po) returned to control values in the E2 supplemented Exercise rats but not in the unsupplemented Exercise group. For example, gastrocnemius Po for OVX HLU, OVX Recovery and OVX-Exercise groups was 82%*, 82%* and 76%* of control. Gastrocnemius Po for E2 supplemented HLU, Recovery and Exercise groups was 72%*, 95% and 106% of control (*P < 0.05 compared to control). H&E cross-sections from OVX-Exercise rats showed central nuclei. In conclusion, a rehabilitation exercise program to remediate acute atrophy in females appears more effective if E2 is present.

Hindlimb skeletal muscle function in myostatin-deficient mice.

Absence of functional myostatin (MSTN) during fetal development results in adult skeletal muscle hypertrophy and hyperplasia. To more fully characterize MSTN loss in hindlimb muscles, the morphology and contractile function of the soleus, plantaris, gastrocnemius, tibialis anterior, and quadriceps muscles in male and female null (Mstn(-/-)), heterozygous (Mstn(+/-)), and wild-type (Mstn(+/+)) mice were investigated. Muscle weights of Mstn(-/-) mice were greater than those of Mstn(+/+) and Mstn(+/-) mice. Fiber cross-sectional area (CSA) was increased in female Mstn(-/-) soleus and gastrocnemius muscles and in the quadriceps of male Mstn(-/-) mice; peak tetanic force in Mstn(-/-) mice did not parallel the increased muscle weight or CSA. Male Mstn(-/-) muscle exhibited moderate degeneration. Visible pathology in male mice and decreased contractile strength relative to increased muscle weight suggest MSTN loss results in muscle impairment, which is dose-, sex-, and muscle-dependent.

White paper: Strength training for the older adult.

The aim of this White Paper was to review the current recommendations for strength training of older adults, to promote physical therapist best practice and achieve optimal functional outcomes. A secondary intent was to encourage prospective researchers to use published guidelines to establish an adequate strength stimulus for patients in their research, rather than perpetuating "usual or traditional" care.

Too many weak days--diagnosis: physical frailty.

Physical frailty is increasing among older adults; half of all those over 85 years are unable to independently accomplish activities of daily living. Gait speed is often compromised which results in diminished functional community independence. This article defines frailty and identifies the risk factors for frailty, as most are modifiable with diet and exercise interventions. Frailty is treatable but ideally, frailty should be prevented as it cannot be cured.

TCAP knockdown by RNA interference inhibits myoblast differentiation in cultured skeletal muscle cells.

Null mutation of titin-cap (TCAP) causes limb-girdle muscular dystrophy type 2G (LGMD2G). LGMD2G patients develop muscle atrophy, and lose the ability to walk by their third decade. Previous findings suggest that TCAP regulates myostatin, a key regulator of muscle growth. We tested the hypothesis that TCAP knockdown with RNA interference will lead to differential expression of genes involved in muscle proliferation and differentiation, impairing muscle cell growth. mRNA from cultured cells treated with TCAP siRNA duplex constructs was analyzed using Northern blots and real-time RT-PCR. siRNA treatment decreased TCAP mRNA expression in differentiating muscle cells. Significant (p<0.05) decreases in mRNA were observed for myogenic regulatory factors. siRNA treatment also prevented development of the normal phenotype of muscle cells. Our findings suggest that TCAP knockdown with RNA interference alters normal muscle cell differentiation.

The effect of ovariectomy combined with hindlimb unloading and reloading on the long bones of mature Sprague-Dawley rats.

OBJECTIVE: To determine the effect of loss of ovarian function and mechanical loading (ie, inactivity) alone or in combination on bone mass and strength. DESIGN: Mature (aged 6 mo) rats were ovariectomized to induce loss of ovarian function and bone. Hindlimb unloading (HLU) was used to determine the effect of mechanical unloading and reloading on bone mass and strength. Bone mass of the femur and tibia was determined using dual-energy x-ray absorptiometry. Femoral and tibial bone strength was determined by a three-point bending test and by a torsion test. RESULTS: Ovariectomy (OVX) alone decreased total bone mineral density (BMD) in the femur (-5.5%, P=0.03) and tibia (-7.3%, P=0.01) compared with that for sham-operated animals. HLU alone for 4 weeks had no significant effect on bone. Together OVX/HLU accentuated BMD loss in the femur (-10.5%, P<0.01) compared with that for sham-operated animals. The femur was more sensitive than the tibia to the combination of OVX/HLU, indicated by the reduction (-5.3%, P<0.05) of total BMD below that achieved by OVX alone. Torsion tests showed that OVX/HLU but not OVX or HLU alone reduced bone strength. There was a correlation between lower femoral total BMD (r2=0.65, P<0.001) and reduced torque strength. Bone loss did not continue during the 2 weeks of reloading. CONCLUSIONS: OVX accompanied by mechanical unloading results in more rapid and severe bone loss than either OVX or unloading alone and therefore is associated with a greater likelihood of osteoporosis.

Skeletal muscle and bone: effect of sex steroids and aging.

Both estrogen and testosterone are present in males and females. Both hormones contribute to the well being of skeletal muscle and bone in men and women, and there is evidence that the loss of sex hormones is associated with the age-related decline in bone and skeletal muscle mass. Hormonal supplementation of older adults to restore estrogen and testosterone levels to those of young men and women is not without penalty.

Exploring Path Models of Disablement in Residential Care and Assisted Living Residents.

This study examined the relationships between individual and environmental factors and physical activity, and between physical activity and functional limitations and disability in residential care/assisted living (RC/AL) residents. Participants completed questionnaires and physical performance tests, and wore the Fitbit Motion Tracker® to capture physical activity. Model fit was analyzed using two-level path models with residents nested within RC/AL settings. Model parameters were estimated using the MPlus robust maximum likelihood method. A multilevel model with good fit (root mean square error of approximation = 0.07, comparative fit index [CFI] = 0.91) showed that persons with greater exercise self-efficacy were more physically active, and persons who were more physically active had better physical function and less disability. Setting-level factors did not significantly correlate with physical activity or disability. Although environmental factors may influence physical activity behavior, only individual factors were associated with physical activity in this sample of RC/AL residents.

Training-induced strength and functional adaptations after hip fracture.

BACKGROUND AND PURPOSE: At 3 months after hip fracture, most people are discharged from physical therapy despite residual muscle weakness and overall decreased functional capabilities. The purposes of this study were: (1) to determine, in frail elderly adults after hip fracture and repair, whether a supervised 6-month exercise program would result in strength gains in the fractured limb equivalent to the level of strength in the nonfractured limb; (2) to determine whether the principle of specificity of training would apply to this population of adults; and (3) to determine the relationship between progressive resistance exercise training (PRT) intensity and changes in measures of strength and physical function. SUBJECTS: The study participants were 31 older adults (9 men and 22 women; age [X+/-SD], 79+/-6 years) who had surgical repair of a hip fracture that was completed less than 16 weeks before study enrollment and who completed at least 30 sessions of a supervised exercise intervention. METHODS: Participants completed 3 months of light resistance and flexibility exercises followed by 3 months of PRT. Tests of strength and function were completed at baseline, before PRT, and after PRT. RESULTS: After PRT, the subjects increased knee extension and leg press 1-repetition maximum by 72%+/-56% and 37%+/-30%, respectively. After 3 and 6 months of training, lower-extremity peak torques all increased. Specificity of training appeared to apply only to the nonfractured limb after PRT. Strong correlations were observed between training intensity and lower-extremity strength gains as well as improvements in measures of physical function. DISCUSSION AND CONCLUSION: Frail elderly adults after hip fracture can benefit by extending their rehabilitation in a supervised exercise setting, working at high intensities in order to optimize gains in strength and physical function.

Ovariectomy prevents the recovery of atrophied gastrocnemius skeletal muscle mass.

The recovery of atrophied muscle mass in animals is thought to be dependent on a number of factors including hormones, cytokines, and/or growth factor expression. The Akt/mammalian target of rapamycin (mTOR) signaling pathway is believed to be activated by these various factors, resulting in skeletal muscle growth through the initiation of protein synthesis. It was hypothesized that surgical removal of the ovaries (Ovx) may alter activation of the Akt/mTOR signaling pathway, a mechanism necessary for muscle regrowth. To test this, 36 Sprague-Dawley rats underwent Ovx or sham surgeries. A portion of the animals were then subjected to hindlimb unloading (HLU) for 28 days. After HLU, one group of Sham and Ovx rats underwent a 14-day recovery period in which the animals were allowed free cage ambulation. The HLU animals demonstrated approximately 21-27% reduction in medial gastrocnemius muscle mass irrespective of whether the ovaries were intact or not. The Sham animals that were reloaded recovered their atrophied muscle mass; however, the Ovx group failed to recover any of the atrophied muscle mass with reloading. The failure to recover muscle mass in the Ovx group was associated with reduced phosphorylation levels of both Akt and p70s6k, whereas in the Sham recovery animals no reductions were found in Akt phosphorylation and significant increases in p70s6k activation were detected. Finally, no differences were detected in mTOR phosphorylation in any of Sham or Ovx groups. These results suggest that ovariectomy surgeries could be detrimental to the recovery of atrophied muscle mass.

Effects of progressive resistance training on body composition in frail older adults: results of a randomized, controlled trial.

BACKGROUND: Progressive resistance exercise training (PRT) has been shown to increase muscle strength and fat-free mass (FFM) in elderly persons. Limited information is available regarding the effects of PRT on lean and fat mass in frail elderly persons. METHODS: Ninety-one community-dwelling sedentary men and women, 78 years and older with physical frailty (defined using standardized objective criteria) were enrolled in a 9-month trial of exercise training (ET). Physical frailty was defined as having 2 of the 3 following criteria: modified Physical Performance Test score between 18 and 32, peak aerobic power between 10 and 18 ml/kg/min, or self-report of difficulty or assistance with two instrumental activities of daily living or one basic activity of daily living. Participants were randomly assigned to either a control (CTL) group that performed a low intensity home exercise program or a supervised ET group that performed 3 months of low intensity exercise and 3 months of PRT. RESULTS: After completion of PRT, ET participants had greater improvements than did CTL participants in maximal voluntary force production for knee extension (mean Delta +5.3 +/- 13 ft/lb vs +1.1 +/- 11 ft/lb, p =.05), measured using isokinetic dynamometry. Total body FFM (measured using dual energy x-ray absorptiometry) increased in the ET group, but not in the CTL group (mean Delta +0.84 +/- 1.4 kg vs +0.01 +/- 1.5 kg, p =.005). Total, trunk, intra-abdominal, and subcutaneous fat mass (measured using dual energy x-ray absorptiometry and (1)H-magnetic resonance imaging) did not change in response to PRT. CONCLUSIONS: Three months of supervised PRT induced improvements in maximal voluntary thigh muscle strength and whole body FFM in frail, community-dwelling elderly women and men. This supervised exercise program may not be sufficient to reduce whole-body or intra-abdominal fat area in this population.

Ovariectomy, hindlimb unweighting, and recovery effects on skeletal muscle in adult rats.

INTRODUCTION: The effect of female sex hormones on skeletal muscle is unclear. Reports suggest that female sex hormones have an anabolic effect, have no effect, or are detrimental to skeletal muscle. METHODS: To amplify ovarian hormones' potential effects on skeletal muscle, 6-mo-old virgin intact (sham), ovariectomized (OVX), and ovariectomized plus estrogen (OVX + E2) rats were hindlimb unweighted (HLU) for 4 wk. To investigate estrogen's influence on the recovery process, OVX-HLU, sham-HLU and OVX + E2 HLU rats were cage-recovered for 2 wk following 4 wk of HLU. Changes in muscle mass were determined for the soleus (SOL), extensor digitorum longus (EDL), quadriceps (QUAD), gastrocnemius (GAST), tibialis anterior (TA), plantaris (PLA), and flexor carpi radialis (FCR). Dry weights were determined for GAST and TA. Peak tetanic tension was ascertained in the postural SOL and locomotor PLA. RESULTS: HLU resulted in a significant (p < 0.05) decline in mass of all muscles studied except EDL and FCR. The magnitude of atrophy resulting from suspension was similar between groups including wet and dry muscle mass normalized to bodyweight. Following HLU there were no differences between intact and OVX rats for contractile characteristics. Reloading for 2 wk resulted in recovery of wet muscle mass in intact and OVX + E2 rats for SOL, PLA, GAST, QUAD, and TA and in dry mass for GAST and TA. Reloaded OVX-HLU rats failed to recover wet muscle mass in all but the SOL and failed to recover GAST and TA dry weight. For example, PLA mass values for intact (sham) rats were 350 +/- 33, 284 +/- 41, and 346 +/- 44 mg for the control, HLU, and recovery groups, respectively. PLA values for OVX rats were 378 +/- 29, 316 +/- 30, and 325 +/- 23 mg for the control, HLU, and recovery groups. DISCUSSION: Results suggest that ovarian function influences the recovery of skeletal muscle mass following a period of reduced physical activity.

Hindlimb Skeletal Muscle Function and Skeletal Quality and Strength in +/G610C Mice With and Without Weight-Bearing Exercise.

Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder associated with reduced bone mineral density and skeletal fragility. Bone is inherently mechanosensitive, with bone strength being proportional to muscle mass and strength. Physically active healthy children accrue more bone than inactive children. Children with type I OI exhibit decreased exercise capacity and muscle strength compared with healthy peers. It is unknown whether this muscle weakness reflects decreased physical activity or a muscle pathology. In this study, we used heterozygous G610C OI model mice (+/G610C), which model both the genotype and phenotype of a large Amish OI kindred, to evaluate hindlimb muscle function and physical activity levels before evaluating the ability of +/G610C mice to undergo a treadmill exercise regimen. We found +/G610C mice hindlimb muscles do not exhibit compromised muscle function, and their activity levels were not reduced relative to wild-type mice. The +/G610C mice were also able to complete an 8-week treadmill regimen. Biomechanical integrity of control and exercised wild-type and +/G610C femora were analyzed by torsional loading to failure. The greatest skeletal gains in response to exercise were observed in stiffness and the shear modulus of elasticity with alterations in collagen content. Analysis of tibial cortical bone by Raman spectroscopy demonstrated similar crystallinity and mineral/matrix ratios regardless of sex, exercise, and genotype. Together, these findings demonstrate +/G610C OI mice have equivalent muscle function, activity levels, and ability to complete a weight-bearing exercise regimen as wild-type mice. The +/G610C mice exhibited increased femoral stiffness and decreased hydroxyproline with exercise, whereas other biomechanical parameters remain unaffected, suggesting a more rigorous exercise regimen or another exercise modality may be required to improve bone quality of OI mice.

Persistent pain in frail older adults after hip fracture repair.

OBJECTIVES: To identify factors associated with persistent hip pain in elderly hip fracture patients with physical frailty. DESIGN: Cohort study. SETTING: Community-based study conducted at academic medical center. PARTICIPANTS: Eighty-eight men and women (mean age+/-standard deviation 80+/-7 years) with a recent hip fracture (mean 14.5+/-4.8 weeks after hip fracture repair) and physical frailty, defined as a modified Physical Performance Test Score between 12 and 28, enrolled in an exercise intervention trial. MEASUREMENTS: Dependent variable was self-report of moderate to severe regional hip pain in the week preceding the baseline interview. Independent variables were self-reported demographic information, health characteristics, and activity of daily living (ADL) function; Yesavage Mood Score (YMS); 36-item Short Form percentile scores; and objective measurements of lower extremity strength, range of motion, balance, and gait. RESULTS: Forty-two percent of the sample reported moderate or severe hip pain at the baseline assessment. Moderate/severe pain was related to difficulty with ADL performance and multiple measures of quality of life. Variables independently associated with moderate/severe hip pain were frequency of pain medication use (adjusted odds ratio (AOR)=5.75, 95% confidence interval (CI)=2.23-14.82, P=.003), YMS score (AOR=2.69, 95% CI=1.18-6.12, P=.02), and knee extension at 60 degrees /s in the fractured limb (AOR=0.96, 95% CI=0.92-1.0, P=.05, model coefficient of determination=0.34). CONCLUSION: Persistent hip pain is a frequent symptom in frail elderly community-dwelling hip fracture patients. Pain medication use, symptoms of depression, and skeletal muscle weakness of the fractured leg are independent correlates of moderate to severe hip pain in this patient population. Clinicians should assess for, and address, persistent pain in this patient population.

Effects of exercise training added to ongoing hormone replacement therapy on bone mineral density in frail elderly women.

OBJECTIVES: To determine whether exercise training added to ongoing hormone replacement therapy (HRT) increases bone mineral density (BMD) in physically frail elderly women. DESIGN: Prospective controlled trial. SETTING: University-based research center. PARTICIPANTS: Twenty-eight women on HRT, aged 75 and older with physical frailty. INTERVENTIONS: Participants were assigned to 9 months of supervised (EXER) or home (HOME) exercise. The EXER program started with physical therapy and gradually incorporated resistance and endurance training. The HOME program consisted of flexibility exercises. MEASUREMENTS: Changes in BMD and body composition. RESULTS: There were larger increases in lumbar spine BMD in response to EXER than with HOME (3.5% vs 1.5%, P =.048), with a trend for larger increases in total body BMD (1.5% vs 0.2%, P =.058). There were no significant between-group differences in hip BMD. The EXER group had decreases in weight (-2.2 +/- 0.3 kg, P =.010) and fat mass (-2.7 +/- 0.4 kg, P =.018) and increases in muscle strength (9-30%, P <.05). CONCLUSION: In physically frail elderly women on HRT, relatively vigorous exercise training significantly increased lumbar spine BMD. The improved BMD and strength in response to exercise could reduce fracture risk in frail women already on HRT.

Effects of exercise training on frailty in community-dwelling older adults: results of a randomized, controlled trial.

OBJECTIVES: Although deficits in skeletal muscle strength, gait, balance, and oxygen uptake are potentially reversible causes of frailty, the efficacy of exercise in reversing frailty in community-dwelling older adults has not been proven. The aim of this study was to determine the effects of intensive exercise training (ET) on measures of physical frailty in older community-dwelling men and women. DESIGN: Randomized controlled trial. SETTING: Medical school research center. PARTICIPANTS: One hundred fifteen sedentary men and women (mean age +/- standard deviation = 83 +/- 4) with mild to moderate physical frailty, as defined by two of the following three criteria: Modified Physical Performance Test (modified PPT) score between 18 and 32, peak oxygen uptake (VO2 peak) between 10 and 18 mL/kg/min, and self-report of difficulty or assistance with one basic activity of daily living (ADL), or two instrumental ADLs. INTERVENTION: Participants were randomly assigned to a control group that performed a 9-month low-intensity home exercise program (control) or an exercise-training program (ET). The control intervention primarily consisted of flexibility exercises. ET began with 3 months of flexibility, light-resistance, and balance training. During the next 3 months, resistance training was added, and, during the next 3 months, endurance training was added. MEASUREMENTS: Modified PPT score, VO2 peak, performance of ADLs as measured by the Older Americans Resources and Services instrument, and the Functional Status Questionnaire (FSQ). RESULTS: ET resulted in significantly greater improvements than home exercise in three of the four primary outcome measures. Adjusted 95% confidence bounds on the magnitude of improvement in the ET group compared with the control group were 1.0 to 5.2 points for the modified PPT score, 0.9 to 3.6 mL/kg/min for VO2 peak, and 1.6 to 4.9 points for the FSQ score. CONCLUSIONS: Our results show that intensive ET can improve measures of physical function and preclinical disability in older adults who have impairments in physical performance and oxygen uptake and are not taking hormone replacement therapy better than a low-intensity home exercise program.