Age-related Loss Of Muscle Mass Research Articles

SUN-P297: The Role of Calcium, Iron, Magnesium, Phosphorus, Potassium, Selenium, Sodium, and Zinc on Muscle Mass, Muscle Strength, and Physical Performance in Older Adults: A Systematic Review

Rationale: Minerals may contribute to prevent and treat sarcopenia, the age-related loss of muscle mass, muscle strength, and physical performance. The aim of this systematic review is to evaluate the role of calcium, iron, magnesium, phosphorus, potassium, selenium, sodium, and zinc on muscle mass, muscle strength, and physical performance in older adults. Methods: A systematic search was conducted between March 2016 and July 2016, in the PubMed database using pre-defined search terms. Articles on the role of dietary mineral intake or mineral serum concentrations on muscle mass, muscle strength, physical performance, and the prevalence of sarcopenia in healthy or frail older adults (average age ≥ 65 years) were selected. Meta-analyses statistic will be performed when possible. Results: From the 3346 articles found, ten studies met the inclusion criteria. Observational studies showed that serum selenium and calcium intake were significantly associated with muscle mass. Magnesium, based on one randomized controlled trial, selenium, iron, and zinc intake were significantly and positively associated with physical performance in older adults. Magnesium, selenium, calcium, and phosphorus intake were associated with the prevalence of sarcopenia. No studies on the role of sodium or potassium on muscle mass, muscle strength, or physical performance were found. Meta-analysis was not possible due to high heterogeneity. Conclusion: Minerals may be important nutrients to prevent and treat sarcopenia. Particularly, magnesium, selenium, and calcium seem to be most promising. Most of the included studies, however, were observational studies. Therefore, more randomized controlled trials are needed to elucidate the potential benefits of mineral intake to prevent and treat sarcopenia and support healthy aging.

P 230 - Simvastatin differently effect oxidative status in cultured myocytes from young and old donors

Sarcopenia is a condition of age-related loss of muscle mass and strength which affects balance, gait and overall ability to perform tasks of daily living, with increased risk of falls. While mitochondrial dysfunction and associated oxidative stress contribute to muscle ageing, the interplay between ROS and protective antioxidant response in the cell is regarded as a key factor in maintaining muscle strength and physical performance. CoQ10 is a lypophilic endogenous cofactor with both antioxidant and bioenergetics function whose levels decrease with age. Moreover also lipid-lowering drugs targeting HMG-CoA reductase (statin) are able to effect CoQ10 synthesis. In the present study we show that murine myocytes (C2C12) exposed to simvastatin 0.3-40 μM for 72 h show a reduced content of CoQ associated with increased ROS production and cytotoxicity. Moreover exposure in the same conditions of primary human myocytes from young and old donors show an enhanced susceptibility to oxidative stress in the elderly a condition that might suggest an enhanced detrimental side effects of statins with potential implications in sarcopenia development.

Computed tomography measured psoas density predicts outcomes in trauma

Age-related loss of muscle mass and function (sarcopenia) is linked to poor outcomes after operation and trauma. Here we evaluate computed tomography measured psoas muscle density and area using quick and simple tools available to the bedside clinician. We hypothesize these measures will predict poor outcomes after blunt traumatic injury. We conducted a retrospective cohort study of patients ages ≥45years in the Ohio State University Trauma Registry in 2008 that received a computed tomographic scan of the abdomen and/or pelvis with intravenous contrast. Psoas Index and Hounsfield unit average calculation were measured at the L3 level. In the study, 90-day mortality, complication, duration of stay ≥7days, and dependent discharge were compared with Psoas Index and Hounsfield unit average calculation. In the study, 151 patients met the inclusion criteria. Patients were stratified into interquartile ranges based either on Psoas Index or Hounsfield unit average calculation values. After adjustment with sex-specific cutoffs, the lowest interquartile range of Psoas Index was associated with 90-day mortality (relative risk [RR] 5.95, P<.008), but did not reach significance in other outcomes. The lowest interquartile range of Hounsfield unit average calculation was associated with 90-day mortality (RR5.95, P<.008), duration of stay≥7days (RR 1.63, P=.048), complication risk (RR 2.30, P=.002), and dependent discharge 2.14, P=.015). Psoas muscle density is a significant predictor of poor outcomes after traumatic injury. This objective, quick, and readily available measure of sarcopenia can identify patients requiring aggressive nutritional and physical therapy to improve prognosis, prevent recurrent traumatic injury, and aid in discharge planning.

Epidemiology of sarcopenia and insight into possible therapeutic targets

Musculoskeletal ageing is a major public health concern owing to demographic shifts in the population. Sarcopenia, generally defined as the age-related loss of muscle mass and function, is associated with considerable risk of falls, loss of independence in older adults and hospitalization with poorer health outcomes. This condition is therefore associated with increased morbidity and health care costs. As with bone mass, muscle mass and strength increase during late adolescence and early adulthood, but begin to decline substantially from ∼50 years of age. Sarcopenia is characterized by many features, which include loss of muscle mass, altered muscle composition, infiltration with fat and fibrous tissue and alterations in innervation. A better understanding of these factors might help us to develop strategies that target these effects. To date, however, methodological challenges and controversies regarding how best to define the condition, in addition to uncertainty about what outcome measures to consider, have delayed research into possible therapeutic options. Most pharmacological agents investigated to date are hormonal, although new developments have seen the emergence of agents that target myostatin signalling to increase muscle mass. In this review we consider the current approaching for defining sarcopenia and discuss its epidemiology, pathogenesis, and potential therapeutic opportunities.

6 Weeks Of Nrf2-activator And Protein Supplementation Improves Myofibrillar Proteostasis In Men.

The age-related loss of muscle mass and function are key contributors to the decline in healthspan. Maintenance of protein homeostasis (proteostasis) is critical to maintain muscle quality and function during advancing age. We have previously shown that interventions that slow aging increase the ratio of skeletal muscle protein to DNA synthesis, which we believe are indicative of improved proteostatic mechanisms. Oxidative stress and inflammation blunt the anabolic response to protein feeding, thus supplementation with a nuclear factor, erythroid 2 like 2 (Nrf2) activator could restore the anabolic response to protein feeding in older adults. PURPOSE: To test the hypothesis that supplementing with a Nrf2 activator alongside protein feeding would increase muscle subcellular protein synthesis in skeletal muscle of older adults. METHODS: In a 6-week double-blind study, older adults (n=46, 60-77 years old) were randomized to protein supplementation with placebo (CON) or one of the Nrf2 activators conjugated linoleic acid (CLA) or Protandim (PTD). We used deuterium-labeled water to measure DNA synthesis and protein synthesis in myofibrillar, mitochondrial, and cytosolic enriched fractions of skeletal muscle. RESULTS: PTD maintained myofibrillar protein synthesis while mitochondrial and cytoplasmic protein synthesis decreased (p<0.05). There was no change in DNA synthesis with PTD or CLA supplementation compared to CON. PTD tended to increase the myofibrillar protein: DNA synthesis ratio compared to CON (PTD 5.55 ± 1.364 vs CON 4.691 ± 0.749; p=0.07). Increased myofibrillar protein:DNA synthesis after PTD was more apparent in men. CONCLUSIONS: We report that protein supplementation with a Nrf2 activator tended to increase myofibrillar protein:DNA synthesis ratio which was more profound in men versus women. Given that protein:DNA synthesis is a measure of proteostasis, our results demonstrate that protein supplementation with a Nrf2 activator to diminish oxidative stress and inflammation improves proteostasis in older adult men. Additional studies are warranted to determine if maintaining myofibrillar proteostasis with PTD or more potent Nrf2 activators may help maintain muscle mass and function with age in both men and women. Supported by the National Dairy Council.

Associations Of Sarcopenia And Low Muscular Strength With All-cause Mortality Among Us Older Adults

Sarcopenia is defined as aging-related loss of muscle mass and knee extension strength serves as a marker of lower extremity muscular strength in populations. Sarcopenia and low muscular strength (LMS) may be important but understudied risk factors for aging-related morbidity and mortality in the older and elderly populations. PURPOSE: We aimed to prospectively examine individual or joint associations of sarcopenia and LMS with all-cause mortality in a nationally representative sample of US older adults in the National Health and Nutrition Examination Survey (NHANES). METHODS: Data sources included the NHANES 1999-2002 with public-use 2011 linked mortality files, which comprised 4,449 participants aged 50 years and older with complete data on body composition by dual-energy x-ray absorptiometry and isokinetic knee extensor strength measurement. Sarcopenia was defined by two definitions proposed by the National Institutes of Health Sarcopenia Project according to appendicular lean mass (ALM) and ALM divided by BMI (ALM/BMI). LMS was defined as the lowest 25% of measurements of knee extensor strength. Weighted multivariable logistic regression models were adjusted for age, sex, race, BMI, smoking, alcohol use, education, leisure time physical activity, sedentary time, and comorbidities. RESULTS: The weighted prevalence of sarcopenia was 23.1% defined by ALM and 17.0% defined by ALM/BMI; the weighted prevalence of low muscular strength was 19.4%. In the multivariate-adjusted models, sarcopenia was significantly associated with increased risk of all-cause mortality for ALM/BMI definition (OR: 1.44; 95% confidence interval [CI], 1.06-1.97) but not for ALM definition (OR: 1.37; 95% CI, 0.90-2.09) while LMS was strongly associated with all-cause mortality (OR: 2.32; 95% CI, 1.70-3.18). In the joint analyses, a significantly increased all-cause mortality was observed only among participants with LMS and non-sarcopenia (OR range: 2.03-2.50) and those with LMS and sarcopenia (OR range: 2.15-2.56) while those without sarcopenia and LMS were the reference group. CONCLUSIONS: Low knee extensor strength indicative of low muscular strength was independently and significantly associated with an increased risk of all-cause mortality among US older adults regardless of the presence or absence of sarcopenia.

Circulating cell-free nucleic acids as potential biomarkers for sarcopenia: a step toward personalized medicine

Sarcopenia is an age-related loss of muscle mass and function, leading to disability, morbidity and increased mortality in older people. Given the relatively high prevalence and related- outcome of the disease, correct diagnosis, screening, monitoring and treatment of sarcopenia are needed in clinical practice. Recent researches have focused on cell-free nucleic acids, which are released into the circulation following cell death, as a potential biomarker of aging and systematic inflammation. It seems that the diagnosis and treatment of sarcopenia can be possible by the help of the analysis of cell-free nucleic acids as noninvasive method.

Jaeumganghwa-Tang, a traditional herbal formula, improves muscle function and attenuates muscle loss in aged mice.

[Purpose]Jaeumganghwa-Tang (JGT), a traditional herbal formula composed of 12 medicinal herbs, is used for the treatment of age-related diseases. In the present study, we investigated the effects of JGT on muscle mass and function in aged mice. [Methods]Young (5-month-old) and old (19-month-old) male C57BL/6 mice were divided into two groups each; one group received JGT (75 mg/d) and the other group received the vehicle for 6 weeks. At the end of the experimental period, muscle strength was examined using the wire hang test, and the tibialis anterior and gastrocnemius muscles were weighed. Muscle samples were further used for histological analysis to assess muscle damage, and the expression of transforming growth factor-beta was investigated via western blotting and immunohistochemistry. [Results]Our results showed that treatment of old mice with JGT improved muscle strength, increased skeletal muscle mass, alleviated muscle damage, and suppressed intramuscular expression of transforming growth factor-beta. [Conclusion]In conclusion, JGT has beneficial effects on age-related loss of muscle mass and function. Thus, it might serve as a potential therapeutic agent for sarcopenia.

Improved skeletal muscle mass and strength after heavy strength training in very old individuals

Age-related loss of muscle mass and function represents personal and socioeconomic challenges. The purpose of this study was to determine the adaptation of skeletal musculature in very old individuals (83+ years) performing 12weeks of heavy resistance training (3×/week) (HRT) compared to a non-training control group (CON). Both groups received similar protein supplementations. We studied 26 participants (86.9±3.2 (SD) (83–94, range) years old) per-protocol. Quadriceps cross-sectional area (CSA) differed between groups at post-test (P<0.05) and increased 1.5±0.7cm2 (3.4%) (P<0.05) in HRT only. The increase in CSA is correlated inversely with the baseline level of CSA (R2=0.43, P<0.02). Thigh muscle isometric strength, isokinetic peak torque and power increased significantly only in HRT by 10–15%, whereas knee extension one-repetition maximum (1 RM) improved by 91%. Physical functional tests, muscle fiber type distribution and size did not differ significantly between groups. We conclude that in protein supplemented very old individuals, heavy resistance training can increase muscle mass and strength, and that the relative improvement in mass is more pronounced when initial muscle mass is low.

Abstract P300: Associations of Sarcopenia and Low Muscular Strength With All-cause Mortality Among US Older Adults: The National Health and Nutrition Examination Surveys 1999-2002

Background: Sarcopenia is defined as aging-related loss of muscle mass and knee extension strength serves as a marker of lower extremity muscular strength in populations. Sarcopenia and low muscular strength (LMS) may be important but understudied risk factors for aging-related morbidity and mortality in the older and elderly populations. However, data from prospective studies are limited. Objective: We aimed to prospectively examine individual or joint associations of sarcopenia and LMS with all-cause mortality in a nationally representative sample of US older adults in the National Health and Nutrition Examination Survey (NHANES). Methods: Data sources included the NHANES 1999-2002 with public-use 2011 linked mortality files, which comprised 4,449 participants aged 50 years and older with complete data on body composition by dual-energy x-ray absorptiometry and isokinetic knee extensor strength measurement. Sarcopenia was defined by two definitions proposed by the National Institutes of Health Sarcopenia Project according to appendicular lean mass (ALM) and ALM divided by BMI (ALM/BMI). LMS was defined as the lowest 25% of measurements of knee extensor strength. Weighted multivariable logistic regression models were used to account for multistage stratified and clustered sampling. Models were adjusted for age, sex, race, BMI, smoking, alcohol use, education, leisure time physical activity, sedentary time, and history of cardiovascular diseases, diabetes, cancer, chronic obstructive pulmonary disease, or chronic kidney disease. Results: Overall, the weighted prevalence of sarcopenia was 23.1% defined by ALM and 17.0% defined by ALM/BMI; the weighted prevalence of low muscular strength was 19.4%. In the multivariate-adjusted models, sarcopenia was significantly associated with increased risk of all-cause mortality for ALM/BMI definition (OR: 1.44; 95% confidence interval [CI], 1.06-1.97) but not for ALM definition (OR: 1.37; 95% CI, 0.90-2.09) while LMS was strongly associated with all-cause mortality (OR: 2.32; 95% CI, 1.70-3.18). In the joint analyses, a significantly increased all-cause mortality was observed only among participants with LMS and non-sarcopenia (OR range: 2.03-2.50) and those with LMS and sarcopenia (OR range: 2.15-2.56) while those without sarcopenia and LMS were the reference group. Conclusions: Low knee extensor strength indicative of low muscular strength was independently and significantly associated with an increased risk of all-cause mortality among US older adults regardless of the presence or absence of sarcopenia.

Influence of skeletal muscles on the risk of falling in old age

Falls in older adults are amajor public health problem, affecting 1 in 3persons aged 65 and over at least once ayear. Consequences of falling include death, injuries, fear of falling, and subsequent loss of independence. The age-related loss of muscle mass and function (sarcopenia) as well as muscle strength are markers of the frailty syndrome. In addition, they are associated with physical function and are a risk factor for falling. Older adults should be screened for falls at least annually. If evaluated as at-risk, acomprehensive falls assessment should be conducted to determine an individual's risk profile. Physical exercise with balance and strength training play akey role in the prevention and management of functional decline and fall risk. Multifactorial interventions are indicated in at-risk individuals. In sarcopenic individuals, sufficient intake of protein must be taken into account and supplementation in combination with exercise appears to be useful.

SIX WEEKS OF DAILY BLUEBERRY CONSUMPTION DOES NOT ALTER AGED SKELETAL MUSCLE INFLAMMATION PROFILE OR INFLAMMATORY RESPONSE TO ECCENTRIC-EXERCISE

Muscles of old adults respond to stress with heightened inflammatory signaling that disrupts the regenerative process. This muscle inflammation susceptibility could contribute to the age-related decline in muscle mass, as anti-inflammatory medications taken concurrently with exercise training, have proven beneficial in attenuating age-related loss of muscle mass. With antioxidants and anti-inflammatory potential, blueberries (BB) are a natural alternative that might regulate aged muscle inflammation susceptibility. Objectives: The purpose of this study was to determine the effects of BB consumption on the muscle inflammatory profile of older adults, and to determine the subsequent muscle inflammatory response to exercise. We hypothesized that BB would lower the inflammatory profile of muscle and attenuate the inflammatory response after resistance exercise. Design: Subjects were randomized to receive daily BB or placebo supplements, which were blind to subjects and researchers. All subjects underwent baseline functional testing, post-supplementation testing, and testing post-muscle stress stimulus. Setting: Volunteers were recruited from Western North Carolina region, USA. Participants: Healthy, non-resistance trained adults over 60 years old (n=22) were recruited. Measurements: Profiles of inflammation pathways known to affect muscle mass were established prior to and after 6-weeks of daily consumption of BB. Post-supplementation, subjects performed an exercise protocol to induce inflammation and returned 24 hours post-exercise to determine the muscle inflammatory profiles. Results: Muscle cytokine and soluble cytokine receptor levels were similar between groups and within groups before and after BB consumption. Cytokine and cytokine receptor levels post-muscle stress changed similarly in the BB and placebo group, indicating BB had no effect on the muscle’s inflammatory response. Total plasma antioxidant capacity was 22% higher in the BB group 24-hours post-muscle stress, however, plasma oxidative stress was not different between groups or within groups. Conclusion: While BB consumption did not affect inflammatory signaling pathways within the muscle nor affect inflammation after a regenerative stimulus, a higher plasma antioxidant capacity could contribute to a better long-term regenerative response.

Association of Coffee Consumption with Sarcopenia in Korean Elderly Men: Analysis Using the Korea National Health and Nutrition Examination Survey, 2008-2011.

BackgroundSarcopenia is an age-related loss of muscle mass and strength. Coffee has antioxidant and anti-inflammatory properties that have been shown to be inversely related to the mechanism of sarcopenia. While there have been some studies on the effect of coffee on sarcopenia in animals, studies on the topic in humans are rare. Therefore, we investigated this relationship in elderly Korean men.MethodsThe cross-sectional data were derived from the 2008–2011 Korea National Health and Nutrition Examination Survey. After applying the exclusion criteria, the study sample consisted of 1,781 men who were at least 60 years of age. Study participants were identified as having sarcopenia if their appendicular skeletal muscle mass divided by height squared was less than two standard deviations below the gender-specific mean of this value for young adults. Daily coffee consumption amounts were categorized as <1 cup, 1 cup, 2 cups, and ≥3 cups.ResultsCompared to the group of individuals who drank less than one cup of coffee a day, people who consumed at least 3 cups (adjusted odds ratio, 0.43; 95% confidence interval, 0.20 to 0.94) showed significantly decreased sarcopenia; however, the decrease was not significant when the daily coffee consumption was 1 or 2 cups. In multivariate logistic regression models, significant associations were observed between sarcopenia and coffee consumption (P for trend=0.039).ConclusionThe results of this study suggest that consuming at least 3 cups of coffee per day was associated with a lower prevalence of sarcopenia in elderly Korean elderly men.

Association between Muscle Mass and Body Mass Index in Elderly Diabetic Patients Attending Tertiary Care Center in Bangalore, India

Background: Sarcopenia is a disorder causing age-related loss of muscle mass. Its multifaceted nature has been linked to an increased risk of disability and mortality. Equally, obesity is a well-known risk factor for a host of disorders. A combination of sarcopenia and obesity in elderly diabetics can synergistically lead to increased insulin resistance and risk of metabolic syndrome. This study aimed to identify the association between sarcopenia and obesity in elderly diabetic patients by a cost-effective anthropometric method. Methods: A case-control study was conducted from January 2016 to April 2016 at Dr. B. R. Ambedkar Medical College in Bangalore. Height, weight, mid-arm circumference, and triceps skin fold thickness of 112 diabetic patients and 131 healthy adults were measured. Descriptive statistical analysis and multiple linear regression analysis were carried out. Results: 26.8% of male and 76.8% of female diabetic patients were obese (body mass index ≥25 kg/m2). Incidence of sarcopenia (muscle mass one standard deviation smaller than healthy reference population, cut-off value for diabetic males being &lt;9.79 kg/m2 and for diabetic females &lt;8.53 kg/m2) were 12.5% in male diabetic patients and 5.4% in female diabetic patients. Conclusion: Sarcopenia and obesity are co-morbid illnesses which can cause functional and metabolic impairments in elderly diabetic patients. There exists a moderate association between muscle mass and body mass index. Loss of muscle strength (dynapenia), rather than loss of muscle mass (sarcopenia), is closely associated with disabilities in these patients.

Physical activity as intervention for age-related loss of muscle mass and function: protocol for a randomised controlled trial (the LISA study)

IntroductionPhysical and cognitive function decline with age, accelerating during the 6th decade. Loss of muscle power (force×velocity product) is a dominant physical determinant for loss of functional ability, especially if...

A combination of Korean mistletoe extract and resistance exercise retarded the decline in muscle mass and strength in the elderly: A randomized controlled trial

Given the increased concerns about the degenerative decline in the physical performance of the elderly, there is a need for developing effective strategies to suppress the age-related loss of skeletal muscle mass and functional capacity through a lifestyle intervention. This randomized controlled trial examined whether a combination of Korean mistletoe extract (KME) supplement and exercise affected muscle mass, muscle function, and targeted molecular expressions. Sixty-seven subjects aged 55–75years were assigned to placebo, low-dose (1g/d), or high-dose (2g/d) of KME for 12weeks. The body composition was significantly changed in the high-dose group during the intervention period as determined by skeletal muscle mass (P=0.040), fat free mass (P=0.042), soft lean mass (P=0.023), skeletal muscle index (P=0.041), fat-free mass index (P=0.030), percent body fat (P=0.044), and fat mass to lean mass ratio (P=0.030). Knee strength was measured by Cybex, demonstrating a significant effect in the KME groups compared to the placebo group (P=0.026 for peak torque and P=0.057 for set total work), which was more pronounced after adjusting for age, gender, protein, and energy intake (P=0.009 for peak torque and P=0.033 for set total work). The dynamic balance ability was remarkably improved in the high-dose group over a 12-week period as determined by Timed “Up and Go” (P=0.005 for fast walk test and P=0.024 for ordinary walk test). Consistent with these results, RT-PCR, multiplex analyses, and immunocytofluorescence staining revealed that a high-dose KME supplementation was effective for suppressing intracellular pathways related to muscle protein degradation, but stimulating those related to myogenesis. In particular, significant differences were found in atrogin-1 mRNA (P=0.002 at a single administration and P=0.001 at a 12-week administration), myogenin mRNA (P<0.0001 at a single administration and P=0.040 at a 12-week administration), and insulin growth factor 1 receptor phosphorylation (P=0.002 at a 12-week administration). These results suggest that KME supplementation together with resistance exercise may be useful in suppressing the age-related loss of muscle mass and strength in the elderly.

181 - The Role of Denervation in Cytokine-Mediated Muscle Dysfunction in Old Mice

Age-related loss of muscle mass and function greatly influences the quality of life of older people. Denervation and increases in pro-inflammatory cytokines are proposed to play a substantial role in this muscle dysfunction. Full denervation of muscle of adult mice causes an increase in the rate of mitochondrial peroxide production1 and data from our laboratory have further demonstrated that this peroxide generation by muscle remained significantly elevated for up to 10 days after denervation, compared with sham controls. Further data suggest that increased mitochondrial peroxide generation may mediate cytokine production by muscle cells2. We hypothesise that the denervation evident in some muscle fibres of old mice results in increased mitochondrial peroxide generation which in turn results in increased production of cytokines by muscle, further contributing to muscle dysfunction. The aim of this study was (1) to use intra-vital imaging in Thy1-CFP mice to examine the structure of peripheral axons and neuromuscular junctions in single muscle fibers in vivo and to monitor H2O2 generation by denervated muscle fibers using AAV6-Hyper2-Cyto injected mice and (2) to examine the effects of increased H2O2 on NF-κB activation and the production of pro-inflammatory cytokines in these fibers. Data demonstrated that the increased mitochondrial peroxide generation in fully denervated muscle of adult mice was associated with activation of NF-κB and increased production of pro-inflammatory cytokines including IL-6, MCP1 and CXCL1. These data suggest that denervation of individual muscle fibers in old mice may result in elevations in H2O2 production in both denervated and innervated fibers and that this may play a role in the increased activation of NF-κB and production of pro-inflammatory cytokines seen in muscles of old mice. Current work focuses on assessment of neuromuscular transmission using electrophysiology in single fibers to determine which age-related changes in neuromuscular junction structure are associated with a lack of neuromuscular activity and cytokine production. References Muller FL, et al 2007. Am J. Physiol. (Reg) 293:R1159-1168. Lightfoot AP, et al 2015. Redox biology. 6:253-259, 2015. Supported by the UK MRC and NIA (AG-20591).

172 - Mitochondrially-Targeted Intervention to Improve Contractile Signaling and Kinetics in Aged Muscle

Exercise is the most effective treatment for sarcopenia, the age-related loss of muscle mass and function. Despite its positive effects, many studies indicate that adaptive signaling with exercise is altered or attenuated with age. We and others have found that aging muscle presents with increased mitochondrial reactive oxygen species (ROS) generation, decreased mitochondrial function, and an oxidized redox status. The extent to which mitochondrial ROS contribute to exercise adaptation and excitation/contraction (EC) coupling remains controversial, but evidence suggests that oxidative modifications to protein thiols may alter the activity of transcription factors, kinases, and the function of contractile proteins. In this study, we hypothesized that an acute decrease in mitochondrial ROS will rescue the age-related changes in skeletal muscle EC coupling and contractile signaling. To test this hypothesis, we performed acute fatiguing contractions using an in vivo stimulation protocol on young (7-10 months) and old (28-32 month) CB6F1 (BALB/cBy x C57BL/6) mice pretreated for one hour with elamipretide (SS-31), a mitochondrially-targeted peptide that reduces mitochondrial ROS and improves bioenergetics in dysfunctional mitochondria. Contraction kinetics were monitored by a force transducer throughout the fatiguing stimulations, and the phosphorylation status of AKT, P38/MAPK, AMPK, and P70S6K were measured in the stimulated and non-stimulated gastrocnemius to address the extent of contractile signaling. Force production was significantly lower in the aged mice compared to young, consistent with sarcopenia. One hour of SS-31 restored the age-related loss of contraction and relaxation rates, but no changes in fatigability or max contraction were observed. In vivo stimulation resulted in significant changes in kinase phosphorylation, however, exercise induced changes in AKT were blunted in aged muscle, but restored with SS-31. Together, these data suggest a direct role of mitochondrial ROS and bioenergetics on EC coupling and kinase activity, and implicate the use of mitochondrially-targeted therapies to improve exercise adaptation in aged muscle.

Light-load resistance exercise increases muscle protein synthesis and hypertrophy signaling in elderly men.

The present study investigated whether well-tolerated light-load resistance exercise (LL-RE) affects skeletal muscle fractional synthetic rate (FSR) and anabolic intracellular signaling as a way to counteract age-related loss of muscle mass. Untrained healthy elderly (>65-yr-old) men were subjected to 13 h of supine rest. After 2.5 h of rest, unilateral LL-RE, consisting of leg extensions (10 sets, 36 repetitions) at 16% of 1 repetition maximum (RM), was conducted. Subsequently, the subjects were randomized to oral intake of 4 g of whey protein per hour (PULSE, n = 10), 28 g of whey protein at 0 h and 12 g of whey protein at 7 h postexercise (BOLUS, n = 10), or 4 g of maltodextrin per hour (placebo, n = 10). Quadriceps muscle biopsies were taken at 0, 3, 7, and 10 h postexercise from the resting and the exercised leg of each subject. Myofibrillar FSR and activity of select targets from the mechanistic target of rapamycin complex 1-signaling cascade were analyzed from the biopsies. LL-RE increased myofibrillar FSR compared with the resting leg throughout the 10-h postexercise period. Phosphorylated (T308) AKT expression increased in the exercised leg immediately after exercise. This increase persisted in the placebo group only. Levels of phosphorylated (T37/46) eukaryotic translation initiation factor 4E-binding protein 1 increased throughout the postexercise period in the exercised leg in the placebo and BOLUS groups and peaked at 7 h. In all three groups, phosphorylated (T56) eukaryotic elongation factor 2 decreased in response to LL-RE. We conclude that resistance exercise at only 16% of 1 RM increased myofibrillar FSR, irrespective of nutrient type and feeding pattern, which indicates an anabolic effect of LL-RE in elderly individuals. This finding was supported by increased signaling for translation initiation and translation elongation in response to LL-RE.

Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle.

Age-related skeletal muscle dysfunction is the underlying cause of morbidity that affects up to half the population aged 80 and over. Considerable evidence indicates that oxidative damage and mitochondrial dysfunction contribute to the sarcopenic phenotype that occurs with aging. To examine this, we administered the mitochondria-targeted antioxidant mitoquinone mesylate {[10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenylphosphonium; 100 μM} to wild-type C57BL/6 mice for 15 wk (from 24 to 28 mo of age) and investigated the effects on age-related loss of muscle mass and function, changes in redox homeostasis, and mitochondrial organelle integrity and function. We found that mitoquinone mesylate treatment failed to prevent age-dependent loss of skeletal muscle mass associated with myofiber atrophy or alter a variety of in situ and ex vivo muscle function analyses, including maximum isometric tetanic force, decline in force after a tetanic fatiguing protocol, and single-fiber-specific force. We also found evidence that long-term mitoquinone mesylate administration did not reduce mitochondrial reactive oxygen species or induce significant changes in muscle redox homeostasis, as assessed by changes in 4-hydroxynonenal protein adducts, protein carbonyl content, protein nitration, and DNA damage determined by the content of 8-hydroxydeoxyguanosine. Mitochondrial membrane potential, abundance, and respiration assessed in permeabilized myofibers were not significantly altered in response to mitoquinone mesylate treatment. Collectively, these findings demonstrate that long-term mitochondria-targeted mitoquinone mesylate administration failed to attenuate age-related oxidative damage in skeletal muscle of old mice or provide any protective effect in the context of muscle aging.—Sakellariou, G. K., Pearson, T., Lightfoot, A. P., Nye, G. A., Wells, N., Giakoumaki, I. I., Griffiths, R. D., McArdle, A., Jackson, M. J. Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle.