Osteoporosis in Frail Older Adults: Recommendations for Research from the ICFSR Task Force 2020.

Interactions among physiological pathways associated with osteoporosis and sarcopenia are thought to contribute to the onset of frailty. The International Conference on Frailty and Sarcopenia Research Task Force thus met in March 2020 to explore how emerging interventions to manage fracture and osteoporosis in older adults may reduce frailty, disability, morbidity, and mortality in the older population. Both pharmacological and non-pharmacological interventions (including nutritional intervention, exercise, and other lifestyle changes) were discussed, including nutritional intervention, exercise, and other lifestyle changes. Pharmacological treatments for osteoporosis include bone-forming and antiresorptive agents, which may optimally be used in sequential or combination regimens. Since similar mechanisms related to resorption underlie physiological changes in muscle and bone, these interventions may provide benefits beyond treating osteoporosis. Clinical trials to test these interventions, however, often exclude frail older persons because of comorbidities (such as mobility disability and cognitive impairment) or polypharmacy. The Task Force recommended that future clinical trials use harmonized protocols, including harmonized inclusion criteria and similar outcome measures; and that they test a range of multidomain therapies. They further advocated more high-quality research to develop interventions specifically for people who are frail and old. The ICOPE program recommended by WHO appears to be highly recommended to frail older adults with osteoporosis.

Circulating Interleukin-6 Is Associated with Skeletal Muscle Strength, Quality, and Functional Adaptation with Exercise Training in Mobility-Limited Older Adults.

BACKGROUND: Human aging is characterized by a chronic, low-grade inflammation suspected to contribute to reductions in skeletal muscle size, strength, and function. Inflammatory cytokines, such as interleukin-6 (IL-6), may play a role in the reduced skeletal muscle adaptive response seen in older individuals. OBJECTIVES: To investigate relationships between circulating IL-6, skeletal muscle health and exercise adaptation in mobility-limited older adults. DESIGN: Randomized controlled trial. SETTING: Exercise laboratory on the Health Sciences campus of an urban university. PARTICIPANTS: 99 mobility-limited (Short Physical Performance Battery (SPPB) ≤9) older adults. INTERVENTION: 6-month structured physical activity with or without a protein and vitamin D nutritional supplement. MEASUREMENTS: Circulating IL-6, skeletal muscle size, composition (percent normal density muscle tissue), strength, power, and specific force (strength/CSA) as well as physical function (gait speed, stair climb time, SPPB-score) were measured pre- and post-intervention. RESULTS: At baseline, Spearman's correlations demonstrated an inverse relationship (P<0.05) between circulating IL-6 and thigh muscle composition (r = -0.201), strength (r = -0.311), power (r = -0.210), and specific force (r = -0.248), and positive association between IL-6 and stair climb time (r = 0.256; P<0.05). Although the training program did not affect circulating IL-6 levels (P=0.69), reductions in IL-6 were associated with gait speed improvements (r = -0.487; P<0.05) in "higher" IL-6 individuals (>1.36 pg/ml). Moreover, baseline IL-6 was inversely associated (P<0.05) with gains in appendicular lean mass and improvements in SPPB score (r = -0.211 and -0.237, respectively). CONCLUSIONS: These findings implicate age-related increases in circulating IL-6 as an important contributor to declines in skeletal muscle strength, quality, function, and training-mediated adaptation. Given the pervasive nature of inflammation among older adults, novel therapeutic strategies to reduce IL-6 as a means of preserving skeletal muscle health are enticing.

Effect of Structured Physical Activity and Nutritional Supplementation on Physical Function in Mobility-Limited Older Adults: Results from the VIVE2 Randomized Trial.

OBJECTIVES: The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). DESIGN: All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). SETTING: Participants were recruited from urban communities at 2 field centers in Boston MA USA and Stockholm SWE. PARTICIPANTS: Mobility-limited (Short Physical Performance Battery (SPPB) ≤9) and vitamin D insufficient (serum 25(OH) D 9 - 24 ng/ml) older adults were recruited for this study. MEASUREMENTS: Primary outcome was gait speed assessed by the 400M walk. RESULTS: 149 subjects were randomized into the study (mean age=77.5±5.4; female=46.3%; mean SPPB= 7.9±1.2; mean 25(OH)D=18.7±6.4 ng/ml). Adherence across supplement and placebo groups was similar (86% and 88%, respectively), and was also similar across groups for the physical activity intervention (75% and 72%, respectively). Both groups demonstrated an improvement in gait speed with no significant difference between those who received the nutritional supplement compared to the placebo (0.071 and 0.108 m/s, respectively (p=0.06)). Similar effects in physical function were observed using the SPPB. Serum 25(OH)D increased in supplemented group compared to placebo 7.4 ng/ml versus 1.3 ng/ml respectively. CONCLUSION: Results suggest improved gait speed following physical activity program with no further improvement with added nutritional supplementation.

Accelerometer Assessment of Physical Activity and Its Association with Physical Function in Older Adults Residing at Assisted Care Facilities.

OBJECTIVES: To describe levels of physical activity among older adults residing at assisted care facilities and their association with physical function. DESIGN: Cross-sectional analysis. SETTING: Assisted care facilities within the greater Boston, MA area. PARTICIPANTS: Older adults aged 65 years and older (N = 65). MEASUREMENTS: Physical Activity Level (PAL) as defined by quartiles from accelerometry (counts and steps), Short Physical Performance Battery (SPPB) Score, gait speed, and handgrip strength. RESULTS: Participants in the most active accelerometry quartile engaged in 25 minutes/week of moderate to vigorous physical activity (MVPA) and walked 2,150 steps/day. These individuals had an SPPB score, 400 meter walk speed, and handgrip strength that was 3.7-3.9 points, 0.3-0.4 meters/second, and 4.5-5.1 kg greater respectively, than individuals in the lowest activity quartile, who engaged in less than 5 min/wk of MVPA or took fewer than 460 steps/day. CONCLUSION: Despite engaging in physical activity levels far below current recommendations (150 min/week of MVPA or > 7000 steps/day), the most active older adults in this study exhibited clinically significant differences in physical function relative to their less active peers. While the direction of causality cannot be determined from this cross-sectional study, these findings suggest a strong association between PAL and physical function among older adults residing in an assisted care facility.

Disseminating a Clinically Effective Physical Activity Program to Preserve Mobility in a Community Setting for Older Adults.

BACKGROUND: As the population of older adults continues to increase, the dissemination of strategies to maintain independence of older persons is of critical public health importance. Recent large-scale clinical trial evidence has definitively shown intervention of moderate-intensity physical activity (PA) reduces major mobility disability in at-risk older adults. However, it remains unknown whether structured PA interventions, with demonstrated efficacy in controlled, clinical environments, can be successfully disseminated into community settings to benefit wider populations of older adults. OBJECTIVE: To assess the dissemination of an evidence-based PA program for older adults by evaluating program participation and its impact on mobility, strength and quality of life. SETTING: An urban senior center. PARTICIPANTS: Fifty older adults (71.2 ± 8 years aged; BMI: 30.1 ± 7 kg/m2). INTERVENTION: Average of 8.0 ± 1.8 months of participation in the Fit-4-Life Program, a community-based PA and nutrition counseling intervention. MEASUREMENTS: Mobility (Short Physical Performance Battery (SPPB)), self-reported physical activity (CHAMPS questionnaire), leg strength, grip strength, and quality of life (Quality of Well-Being Self-Administered (QWB-SA) scale) were assessed at baseline and follow-up. RESULTS: Mean attendance was 55.8%. Fourteen participants were lost to follow-up. Those who dropped-out engaged in less PA at baseline (78 ± 108 mins/wk) compared to those who completed follow-up (203 ± 177 mins/wk, P=0.01). Participants exhibited sustained increases of PA (65 ± 153 mins/wk, P= 0.08), and there were meaningful improvements in SPPB (0.5 ± 0.2, P< 0.01), knee extensor strength (2.6 ± 4.4 kg, P< 0.01) and QWB-SA (0.04 ± 0.09, P= 0.05). CONCLUSION: The dissemination of a clinically efficacious PA intervention into a community-based setting can improve mobility, strength and quality of life for older adults. This knowledge may be helpful for the design and implementation of larger-scale PA intervention studies designed to preserve mobility in older adults within community-based settings.

Collaborative Evaluation of the Healthy Habits Program: An Effective Community Intervention to Improve Mobility and Cognition of Chinese Older Adults Living in the U.S.

OBJECTIVES: There is a growing demand to reduce ethnic health disparities. The Healthy Habits Program (HHP) was implemented to provide a community-based physical activity and education intervention for Chinese older adults living in Boston, Massachusetts. This study evaluated the HHP by assessing outcomes that are critical for maintaining independence of older persons. DESIGN, SETTING AND PARTICIPANTS: Quantitative evaluation was performed on 50 Chinese older adults enrolled in the HHP. The community members were trained in data collection and management. MEASUREMENTS: Cognition (Mini Mental State Examination (MMSE), Trail Making Test and Complex Walking Task), mobility (Short Physical Performance Battery (SPPB) and maximal gait speed), depressive symptoms (Patient Health Questionnaire-9), perceived disability (World Health Organization Disability Assessment 2.0), nutritional status (Mini Nutrition Assessment®), and strength (grip and leg strength) were assessed at baseline and at 6 months. All tests were translated into Chinese. RESULTS: Of the 50 participants (mean age 68.4 years; 68% female), 78% achieved the goal of performing exercise ≥3 times/week. After 6 months, clinically meaningful improvements were observed in mobility (mean SPPB score changed from 10.3 to 11.1 points; p=0.01) and cognition (mean MMSE score changed from 26.0 to 27.8 points; p=0.001). There were also statistically significant improvements in executive function, depressive symptoms and perceived disability (p<0.05). CONCLUSION: Culturally sensitive community interventions, such as the HHP, are effective for improving mobility and cognition of Chinese older adults. This reveals the potential of promoting successful aging in minority populations through community settings, and should be advocated to reduce ethnic health disparities in the U.S.

The impact of sarcopenia on a physical activity intervention: the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P).

OBJECTIVE: To determine if sarcopenia modulates the response to a physical activity intervention in functionally limited older adults. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Three academic centers. PARTICIPANTS: Elders aged 70 to 89 years at risk for mobility disability who underwent dual-energy x-ray absorptiometry (DXA) for body composition at enrollment and follow-up at twelve months (N = 177). INTERVENTION: Subjects participated in a physical activity program (PA) featuring aerobic, strength, balance, and flexibility training, or a successful aging (SA) educational program about healthy aging. MEASUREMENTS: Sarcopenia as determined by measuring appendicular lean mass and adjusting for height and total body fat mass (residuals method), Short Physical Performance Battery score (SPPB), and gait speed determined on 400 meter course. RESULTS: At twelve months, sarcopenic and non-sarcopenic subjects in PA tended to have higher mean SPPB scores (8.7±0.5 and 8.7±0.2 points) compared to sarcopenic and non-sarcopenic subjects in SA (8.3±0.5 and 8.4±0.2 points, p = 0.24 and 0.10), although the differences were not statistically significant. At twelve months, faster mean gait speeds were observed in PA: 0.93±0.4 and 0.95±0.03 meters/second in sarcopenic and non-sarcopenic PA subjects, and 0.89±0.4 and 0.91±0.03 meters/second in sarcopenic and non-sarcopenic SA subjects (p = 0.98 and 0.26), although not statistically significant. There was no difference between the sarcopenic and non-sarcopenic groups in intervention adherence or number of adverse events. CONCLUSION: These data suggest that older adults with sarcopenia, who represent a vulnerable segment of the elder population, are capable of improvements in physical performance after a physical activity intervention.

Lipogenic regulators are elevated with age and chronic overload in rat skeletal muscle.

AIM: Both muscle mass and strength decline with ageing, but the loss of strength far surpasses what is projected based on the decline in mass. Interestingly, the accumulation of fat mass has been shown to be a strong predictor of functional loss and disability. Furthermore, there is a known attenuated hypertrophic response to skeletal muscle overload with ageing. The purpose of this study was to determine the effect of 28 days of overload on the storage of intramuscular triglycerides (IMTG) and metabolic regulators of lipid synthesis in young and old skeletal muscle. METHODS: The phosphorylation and expression of essential lipogenic regulators were determined in the plantaris of young (YNG; 6-month-old) and aged (OLD; 30-month-old) rats subjected to bilateral synergist ablation (SA) of two-thirds of the gastrocnemius muscle or sham surgery. RESULTS: We demonstrate that age-induced increases in IMTG are associated with enhancements in the expression of lipogenic regulators in muscle. We also show that the phosphorylation and concentration of the 5'AMP-activated protein kinase (AMPK) isoforms are altered in OLD. We observed increases in the expression of lipogenic regulators and AMPK signalling after SA in YNG, despite no increase in IMTG. Markers of oxidative capacity were increased in YNG after SA. These overload-induced effects were blunted in OLD. CONCLUSION: These data suggest that lipid metabolism may be altered in ageing skeletal muscle and is unaffected by mechanical overload via SA. By determining the role of increased lipid storage on skeletal muscle mass during ageing, possible gene targets for the treatment of sarcopenia may be identified.

Eccentric exercise markedly increases c-Jun NH(2)-terminal kinase activity in human skeletal muscle.

Eccentric contractions require the lengthening of skeletal muscle during force production and result in acute and prolonged muscle injury. Because a variety of stressors, including physical exercise and injury, can result in the activation of the c-Jun NH(2)-terminal kinase (JNK) intracellular signaling cascade in skeletal muscle, we investigated the effects of eccentric exercise on the activation of this stress-activated protein kinase in human skeletal muscle. Twelve healthy subjects (7 men, 5 women) completed maximal concentric or eccentric knee extensions on a KinCom isokinetic dynamometer (10 sets, 10 repetitions). Percutaneous needle biopsies were obtained from the vastus lateralis muscle 24 h before exercise (basal), immediately postexercise, and 6 h postexercise. Whereas both forms of exercise increased JNK activity immediately postexercise, eccentric contractions resulted in a much higher activation (15.4 +/- 4.5 vs. 3.5 +/- 1.4-fold increase above basal, eccentric vs. concentric). By 6 h after exercise, JNK activity decreased back to baseline values. In contrast to the greater activation of JNK with eccentric exercise, the mitogen-activated protein kinase kinase 4, the immediate upstream regulator of JNK, was similarly activated by concentric and eccentric exercise. Because the activation of JNK promotes the phosphorylation of a variety of transcription factors, including c-Jun, the results from this study suggest that JNK may be involved in the molecular and cellular adaptations that occur in response to injury-producing exercise in human skeletal muscle.

Effects of creatine supplementation on the energy cost of muscle contraction: a 31P-MRS study.

Five women and 3 men (29.8 +/- 1.4 yr) performed dynamic knee-extension exercise inside a magnetic resonance system (means +/- SE). Two trials were performed 7-14 days apart, consisting of a 4- to 5-min exhaustive exercise bout. To determine quadriceps cost of contraction, brief static and dynamic contractions were performed pre- and postexercise. (31)P spectra were used to determine pH and relative concentrations of P(i), phosphocreatine (PCr), and betaATP. Subjects consumed 0.3 g. kg(-1). day(-1) of a placebo (trial 1) or creatine (trial 2) for 5 days before each trial. After creatine supplementation, resting DeltaPCr increased from 40.7 +/- 1.8 to 46. 6 +/- 1.1 mmol/kg (P = 0.04) and PCr during exercise declined from -29.6 +/- 2.4 to -34.1 +/- 2.8 mmol/kg (P = 0.02). Muscle static (DeltaATP/N) and dynamic (DeltaATP/J) costs of contraction were unaffected by creatine supplementation as well as were ATP, P(i), pH, PCr resynthesis rate, and muscle strength and endurance. DeltaATP/J and DeltaATP/N were greatest at the onset of the exercise protocol (P < 0.01). In summary, creatine supplementation increased muscle PCr concentration, which did not affect muscle ATP cost of contraction.

Insulin-like growth factor I in skeletal muscle after weight-lifting exercise in frail elders.

To assess muscle remodeling and functional adaptation to exercise and diet interventions, 26 men and women aged 72-98 yr underwent a vastus lateralis biopsy before and after placebo control condition, and progressive resistance training, multinutrient supplementation, or both. Type II atrophy, Z band, and myofibril damage were present at baseline. Combined weight lifting and nutritional supplementation increased strength by 257 +/- 62% (P = 0.0001) and type II fiber area by 10.1 +/- 9.0% (P = 0.033), with a similar trend for type I fiber area (+12.8 +/- 22.2%). Exercise was associated with a 2. 5-fold increase in neonatal myosin staining (P = 0.0009) and an increase of 491 +/- 137% (P < 0.0001) in IGF-I staining. Ultrastructural damage increased by 141 +/- 59% after exercise training (P = 0.034). Strength increases were largest in those with the greatest increases in myosin, IGF-I, damage, and caloric intake during the trial. Age-related sarcopenia appears largely confined to type II muscle fibers. Frail elders respond robustly to resistance training with musculoskeletal remodeling, and significant increases in muscle area are possible with resistance training in combination with adequate energy intakes.

Creatine supplementation and age influence muscle metabolism during exercise.

Young [n = 5, 30 +/- 5 (SD) yr] and middle-aged (n = 4, 58 +/- 4 yr) men and women performed single-leg knee-extension exercise inside a whole body magnetic resonance system. Two trials were performed 7 days apart and consisted of two 2-min bouts and a third bout continued to exhaustion, all separated by 3 min of recovery. 31P spectra were used to determine pH and relative concentrations of Pi, phosphocreatine (PCr), and beta-ATP every 10 s. The subjects consumed 0.3 g . kg-1 . day-1 of a placebo (trial 1) or creatine (trial 2) for 5 days before each trial. During the placebo trial, the middle-aged group had a lower resting PCr compared with the young group (35.0 +/- 5.2 vs. 39.5 +/- 5.1 mmol/kg, P < 0.05) and a lower mean initial PCr resynthesis rate (18.1 +/- 3.5 vs. 23.2 +/- 6.0 mmol . kg-1 . min-1, P < 0.05). After creatine supplementation, resting PCr increased 15% (P < 0.05) in the young group and 30% (P < 0.05) in the middle-aged group to 45.7 +/- 7.5 vs. 45.7 +/- 5.5 mmol/kg, respectively. Mean initial PCr resynthesis rate also increased in the middle-aged group (P < 0.05) to a level not different from the young group (24.3 +/- 3.8 vs. 24.2 +/- 3.2 mmol . kg-1 . min-1). Time to exhaustion was increased in both groups combined after creatine supplementation (118 +/- 34 vs. 154 +/- 70 s, P < 0.05). In conclusion, creatine supplementation has a greater effect on PCr availability and resynthesis rate in middle-aged compared with younger persons.

Extracellular-regulated protein kinase cascades are activated in response to injury in human skeletal muscle.

The mitogen-activated protein (MAP) kinase signaling pathways are believed to act as critical signal transducers between stress stimuli and transcriptional responses in mammalian cells. However, it is not known whether these signaling cascades also participate in the response to injury in human tissues. To determine whether injury to the vastus lateralis muscle activates MAP kinase signaling in human subjects, two needle biopsies or open muscle biopsies were taken from the same incision site 30-60 min apart. The muscle biopsy procedures resulted in striking increases in dual phosphorylation of the extracellular-regulated kinases (ERK1 and ERK2) and in activity of the downstream substrate, the p90 ribosomal S6 kinase. Raf-1 kinase and MAP kinase kinase, upstream activators of ERK, were also markedly stimulated in all subjects. In addition, c-Jun NH2-terminal kinase and p38 kinase, components of two parallel MAP kinase pathways, were activated following muscle injury. The stimulation of the three MAP kinase cascades was present only in the immediate vicinity of the injury, a finding consistent with a local rather than systemic activation of these signaling cascades in response to injury. These data demonstrate that muscle injury induces the stimulation of the three MAP kinase cascades in human skeletal muscle, suggesting a physiological relevance of these protein kinases in the immediate response to tissue injury and possibly in the initiation of wound healing.

Exercise stimulates the mitogen-activated protein kinase pathway in human skeletal muscle.

Physical exercise can cause marked alterations in the structure and function of human skeletal muscle. However, little is known about the specific signaling molecules and pathways that enable exercise to modulate cellular processes in skeletal muscle. The mitogen-activated protein kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular signals into intracellular responses. We tested the hypothesis that a single bout of exercise activates the MAPK signaling pathway. Needle biopsies of vastus lateralis muscle were taken from nine subjects at rest and after 60 min of cycle ergometer exercise. In all subjects, exercise increased MAPK phosphorylation, and the activity of its downstream substrate, the p90 ribosomal S6 kinase 2. Furthermore, exercise increased the activities of the upstream regulators of MAPK, MAP kinase kinase, and Raf-1. When two additional subjects were studied using a one-legged exercise protocol, MAPK phosphorylation and p90 ribosomal S6 kinase 2, MAP kinase kinase 1, and Raf-1 activities were increased only in the exercising leg. These studies demonstrate that exercise activates the MAPK cascade in human skeletal muscle and that this stimulation is primarily a local, tissue-specific phenomenon, rather than a systemic response to exercise. These findings suggest that the MAPK pathway may modulate cellular processes that occur in skeletal muscle in response to exercise.

The role of progressive resistance training and nutrition in the preservation of lean body mass in the elderly.

Human aging is associated with an increased incidence of several chronic diseases including coronary artery disease, non insulin-dependent diabetes mellitus and osteoporosis. Concurrent with the increased prevalence of these diseases in the elderly are well-documented changes in body composition that include an increased fat mass and a progressive decline in skeletal muscle mass and bone mineral density. Together these factors result in age-related decreases in muscle strength and aerobic capacity which contribute to decreases in functional independence. Progressive resistance (strength) training interventions have been proposed as countermeasures to some of these degenerative processes. Recently, several studies have reported on the effects of high intensity resistance training on muscle function and size in both healthy middle-aged men and women (50-75 years) and older frail men and women (80-100 years). In total, the majority of these studies have shown substantial increases (> 100%) in the one repetition maximum muscle strength of the muscle's being exercised in response to 8 to 12 weeks of strength training (3 to 4 times per week at 70 to 90% of the 1 repetition maximum). In addition, a subset of these reports has also reported significant increases in muscle size either by computed tomography (CT) analysis of muscle cross-sectional area (9 to 17%) or by biopsy examination of muscle fiber size changes (20 to 30%). There is now compelling evidence that progressive resistance training in the elderly can positively influence whole body energy expenditure, muscle growth, and function. In addition, strength training interventions may be a powerful tool in the prevention of age-associated sarcopenia (loss of muscle mass).

Relationships between in vivo and in vitro measurements of metabolism in young and old human calf muscles.

This study compared in vivo measurements of muscle metabolism in humans with magnetic resonance spectroscopy (MRS) and in vitro analysis of biopsies. Healthy subjects [4 young males, 28.2 +/- 6.8 (SD) yr, and 6 older subjects (5 males, 1 female), 66 +/- 6.0 yr] performed a maximal cycle ergometer test, and MRS measurements of the calf muscles and needle biopsies of the lateral gastrocnemius were performed. Biopsies were analyzed for fiber type and citrate synthase (CS) activity. MRS measurements of inorganic phosphate (Pi), phosphocreatine (PCr), ATP, and pH were made using a 1.8-T 78-cm clear-bore magnet-and-spectrometer system. Two or three 5-min bouts of plantar flexion were performed against variable resistance to deplete PCr levels to 50% of resting values (mean end pH 6.99). PCr values during recovery were fit to an exponential curve, and the rate constant (PCrrate) was calculated. PCrrate was used as an index of oxidative metabolism. Older subjects had lower peak O2 uptake (VO2 peak) values (19.2 +/- 5.6 vs. 49.5 +/- 8.1 ml O2.min-1 x kg-1), CS activities (16 +/- 2.8 vs. 25 +/- 2.6 mmol.kg wet wt-1 x min-1), and PCrrate values (25.3 +/- 8. vs. 37.5 +/- 5.3 mmol PCr.kg wet wt-1.min-1) than young subjects. PCrrate correlated with CS activity, and both PCrrate and CS activity correlated with VO2 peak (P < 0.05). No correlations were found between percent fiber type and PCrrate, CS activity, and VO2 peak. These results support studies that showed decreases in muscle metabolism with age in healthy humans and show a good correlation between in vivo and in vitro measurements of oxidative metabolism.

Exercise increases muscle GLUT-4 levels and insulin action in subjects with impaired glucose tolerance.

A decline in insulin sensitivity is associated with aging, inactivity, and obesity. The effects of exercise training on glucose homeostasis independent of weight loss in older glucose-intolerant individuals are not well established. We examined the effects of exercise training on oral glucose tolerance, insulin action, and concentration of the GLUT-4 glucose transporters in skeletal muscle. Exercise training at 50 and 75% of heart rate reserve was performed for 12 wk in 18 individuals (age = 64 +/- 2, body fat = 37.0 +/- 1.5%). Peripheral insulin action was determined 96 h after the last exercise bout using a two-step hyperinsulinemic-euglycemic glucose clamp (insulin = 192 and 708 pmol/l). Percent body fat and fat-free mass (FFM) were unchanged with training. Diet composition, assessed by diet record, did not change over the 12 wk. Improved oral glucose tolerance was observed, as exhibited by lower plasma glucose concentrations after training (P < 0.05), whereas plasma insulin response remained unchanged. The rate of glucose disposal was unchanged during the low insulin concentration but increased 11.0% at the high insulin concentration (P < 0.05) after training (54.4 +/- 4.4 vs. 60.4 +/- 5.5 mumol.kg FFM-1.min-1). Skeletal muscle glycogen and GLUT-4 concentration increased 24 and 60%, respectively, with training. There was no direct relationship between the change in GLUT-4 protein and the change in glucose disposal rate. These findings demonstrate that chronic exercise training without changes in body composition improves peripheral insulin action in subjects with impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of vitamin E on exercise-induced oxidative damage in young and older adults.

The protective effect of vitamin E supplementation on exercise-induced oxidative damage was tested in 21 male volunteers. Nine young (22-29 yr) and 12 older (55-74 yr) sedentary male subjects participated in a double-blind protocol and received either 800 IU dl-alpha-tocopherol or a placebo daily. After 48 days, vitamin E supplementation significantly increased alpha-tocopherol in plasma and skeletal muscle. Subjects then performed a bout of eccentric exercise at 75% of their maximum heart rate by running down an inclined treadmill for 45 min. All vitamin E-supplemented subjects excreted less (P < 0.05) urinary thiobarbituric acid adducts after the exercise bout than placebo subjects at 12 days postexercise (35 and 18% above baseline in young and old supplemented groups, respectively, vs. 60 and 80% in young and old placebo groups, respectively). After exercise, the initial difference in alpha-tocopherol concentration of muscle between young placebo and vitamin E-supplemented groups was diminished and muscle lipid conjugated dienes tended to increase (P = 0.09) in placebo subjects. Placebo subjects had a significant decrease in major fatty acids of muscle biopsy taken immediately after exercise. When normalized for the hemoconcentration effects of exercise, the plasma concentration of vitamins E and C and uric acid showed no significant change. The alterations in fatty acid composition, vitamin E, and lipid conjugated dienes in muscle and in urinary lipid peroxides in controls after eccentric exercise are consistent with the concept that vitamin E provides protection against exercise-induced oxidative injury.

Acute phase response in exercise. II. Associations between vitamin E, cytokines, and muscle proteolysis.

Cytokines such as interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6) mediate a variety of host responses to trauma and infection, including skeletal muscle proteolysis. This investigation assesses the influence of damaging eccentric exercise on in vitro production and plasma concentrations of cytokines and their relationship to muscle protein breakdown. In a double-blind placebo-controlled protocol, 21 male subjects took vitamin E supplements (800 IU/day) for 48 days, then ran downhill on an inclined treadmill. Twenty-four hours after this single session of eccentric exercise, endotoxin-induced secretion of IL-1 beta was augmented 154% (P less than 0.01) in cells obtained from the placebo subjects, but no significant exercise-related changes were observed in cells from the vitamin E-supplemented subjects. TNF-alpha secretion was also significantly increased 24 h after exercise, but the response was not inhibited by vitamin E. In contrast, IL-6 secretion did not change after exercise, but dietary vitamin E supplementation significantly reduced IL-6 secretion throughout the 12-day period of observation (P = 0.023). Urinary 3-methylhistidine excretion correlated with mononuclear cell secretion of both IL-1 beta (P less than 0.05) and prostaglandin E2 (P less than 0.05), supporting the concept that these mononuclear cell products contribute to the regulation of muscle proteolysis.

Increased interleukin 1 beta in human skeletal muscle after exercise.

Interleukin 1 beta (IL-1 beta) is a protein released from blood monocytes and related cells in response to infectious or inflammatory stimuli. Although IL-1 beta is elevated in the circulation for only a few hours after an acute inflammatory challenge or exercise, it has been proposed to mediate anabolic and catabolic processes that can last for several days. In this report, eccentric exercise was used as a noninfectious inflammatory stimulus. IL-1 beta was found in muscle tissue up to 5 days after exercise using specific immunohistochemical tissue staining. Increased IL-1 beta immunoreactivity was observed in muscle tissue from four human subjects who performed the exercise, but not in tissue obtained at the same time intervals from two subjects who did not exercise. Little immunohistochemical evidence of interleukin-1 alpha or tumor necrosis factor alpha was observed before or after exercise. These results implicate IL-1 beta in the metabolic adaptations of muscle tissue, which occur in response to noninfectious stresses.