Thomas W. Buford

Models of Accelerated Sarcopenia: Critical Pieces for Solving the Puzzle of Age-Related Muscle Atrophy

Sarcopenia, the age-related loss of skeletal muscle mass, is a significant public health concern that continues to grow in relevance as the population ages. Certain conditions have the strong potential to coincide with sarcopenia to accelerate the progression of muscle atrophy in older adults. Among these conditions are co-morbid diseases common to older individuals such as cancer, kidney disease, diabetes, and peripheral artery disease. Furthermore, behaviors such as poor nutrition and physical inactivity are well-known to contribute to sarcopenia development. However, we argue that these behaviors are not inherent to the development of sarcopenia but rather accelerate its progression. In the present review, we discuss how these factors affect systemic and cellular mechanisms that contribute to skeletal muscle atrophy. In addition, we describe gaps in the literature concerning the role of these factors in accelerating sarcopenia progression. Elucidating biochemical pathways related to accelerated muscle atrophy may allow for improved discovery of therapeutic treatments related to sarcopenia.

International Society of Sports Nutrition position stand: creatine supplementation and exercise.

Email: Thomas W Buford thomas_buford@baylor.edu; Richard B Kreider* Richard_Kreider@baylor.edu; Jeffrey R Stout jrstout@ou.edu; Mike Greenwood Mike_Greenwood@baylor.edu; Bill Campbell Campbell@coedu.usf.edu; Marie Spano mariespano@comcast.net; Tim Ziegenfuss tim@ohioresearchgroup.com; Hector Lopez hlopezmd@gmail.com; Jamie Landis jlandis@lakelandcc.edu; Jose Antonio exphys@aol.com * Corresponding author

Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials.

Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes - including oxidative stress, quality control mechanisms and apoptotic signaling - on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

The Impact of Aging on Mitochondrial Function and Biogenesis Pathways in Skeletal Muscle of Sedentary High- and Low-Functioning Elderly Individuals

Age‐related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high‐ and low‐functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low‐functioning elderly (LFE) participants when compared to young and high‐functioning elderly participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in cytochrome c oxidase activity. Levels of key metabolic regulators, SIRT3 and PGC‐1α, were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects; however, no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.

Effects of acute and 14-day coenzyme Q10 supplementation on exercise performance in both trained and untrained individuals

BackgroundTo determine whether acute (single dose) and/or chronic (14-days) supplementation of CoQ10 will improve anaerobic and/or aerobic exercise performance by increasing plasma and muscle CoQ10 concentrations within trained and untrained individuals.MethodsTwenty-two aerobically trained and nineteen untrained male and female subjects (26.1 ± 7.6 yrs, 172 ± 8.7 cm, 73.5 ± 17 kg, and 21.2 ± 7.0%) were randomized to ingest in a double-blind manner either 100 mg of a dextrose placebo (CON) or a fast-melt CoQ10 supplement (CoQ10) twice a day for 14-days. On the first day of supplementation, subjects donated fasting blood samples and a muscle biopsy. Subjects were then given 200 mg of the placebo or the CoQ10 supplement. Sixty minutes following supplement ingestion, subjects completed an isokinetic knee extension endurance test, a 30-second wingate anaerobic capacity test, and a maximal cardiopulmonary graded exercise test interspersed with 30-minutes of recovery. Additional blood samples were taken immediately following each exercise test and a second muscle biopsy sample was taken following the final exercise test. Subjects consumed twice daily (morning and night), 100 mg of either supplement for a period of 14-days, and then returned to the lab to complete the same battery of tests. Data was analyzed using repeated measures ANOVA with an alpha of 0.05.ResultsPlasma CoQ10 levels were significantly increased following 2 weeks of CoQ10 supplementation (p < 0.001); while a trend for higher muscle CoQ10 levels was observed after acute CoQ10 ingestion (p = 0.098). A trend for lower serum superoxide dismutase (SOD) was observed following acute supplementation with CoQ10 (p = 0.06), whereas serum malondialdehyde (MDA) tended to be significantly higher (p < 0.05). Following acute ingestion of CoQ10, plasma CoQ10 levels were significantly correlated to muscle CoQ10 levels; maximal oxygen consumption; and treadmill time to exhaustion. A trend for increased time to exhaustion was observed following 2 weeks of CoQ10 supplementation (p = 0.06).ConclusionAcute supplementation with CoQ10 resulted in higher muscle CoQ10 concentration, lower serum SOD oxidative stress, and higher MDA levels during and following exercise. Chronic CoQ10 supplementation increased plasma CoQ10 concentrations and tended to increase time to exhaustion. Results indicate that acute and chronic supplementation of CoQ10 may affect acute and/or chronic responses to various types of exercise.

A comparison of periodization models during nine weeks with equated volume and intensity for strength.

The purpose of the present investigation was to determine if significant differences exist among 3 different periodization programs in eliciting changes in strength. Twenty-eight recreationally trained college-aged volunteers (mean = SD; 22.29 = 3.98) of both genders were tested for bench press, leg press, body fat percentage, chest circumference, and thigh circumference during initial testing. After initial testing, subjects were randomly assigned to 1 of 3 training groups: (a) linear periodization (n = 9), (b) daily undulating periodization (n = 10), or (c) weekly undulating periodization (n = 9). The training regimen for each group consisted of a 9-week, 3-day-per-week program. Training loads were assigned as heavy (90%, 4 repetition maximum [4RM]), medium (85%, 6RM), or light (80%, 8RM) for bench press and leg press exercises. Subjects were familiarized with the CR-10 rated perceived exertion scale and instructed to achieve an 8 or 9 on the final repetition of each set for all other exercises. Subjects were then retested after 4 weeks of training. Training loads were then adjusted according to the new 1RM. Subjects were then retested after 5 more weeks of exercise. For all subjects, significant (p < 0.05) increases in bench press and leg press strength were demonstrated at all time points (T1–T3). No significant differences (p > 0.05) were observed between groups for bench press, leg press, body fat percentage, chest circumference, or thigh circumference at all time points. These results indicate that no separation based on periodization model is seen in early-phase training.

Impact of DHEA(S) and cortisol on immune function in aging : a brief review

A decline in the human immune system that occurs with aging is known as immunosenescence. Several factors are involved in the process, including reduced neutrophil function and cytotoxic capacity of natural killer (NK) cells, thymus atrophy and reduced naïve T cell number, and lowered B cell antibody production in response to antigen. The endocrine system, specifically the hypothalamus-pituitary-adrenal axis, plays an important role in modulating immune function. With aging an imbalance occurs between two adrenal hormones, cortisol and DHEA, that have opposing actions on immune function. This brief review explores the interactions between cortisol and DHEA and their effects on immune function in aging, as well as potential methods to combat the endocrine-related contribution to immunosenescence, including DHEA supplementation and exercise.

Age-related Differences in Lower Extremity Tissue Compartments and Associations with Physical Function in Older Adults

The lower extremities are important to performing physical activities of daily life. This study investigated lower extremity tissue composition, i.e. muscle and fat volumes, in young and older adults and the relative importance of individual tissue compartments to the physical function of older adults. A total of 43 older (age 78.3±5.6 years) and 20 younger (age 23.8±3.9 years) healthy men and women participated in the study. Older participants were further classified as either high- (HF) or low-functioning (LF) according to the Short Physical Performance Battery (SPPB). Magnetic resonance images were used to determine the volumes of skeletal muscle, subcutaneous fat (SAT), and intermuscular fat (IMAT) in the thigh (femoral) and calf (tibiofibular) regions. After adjusting for the sex of participants, younger participants had more femoral muscle mass than older adults (p<0.001 for between group differences) as well as less femoral IMAT (p=0.008) and tibiofibular IMAT (p<0.001). Femoral muscle was the only tissue compartment demonstrating a significant difference between the two older groups, with HF participants having 31% more femoral muscle mass than LF participants (mean difference=103.0±34.0 cm(3); p=0.011). In subsequent multiple regression models including tissue compartments and demographic confounders, femoral muscle was the primary compartment associated with both SPPB score (r(2)=0.264, p=0.001) and 4-meter gait speed (r(2)=0.187, p=0.007). These data suggest that aging affects all lower extremity compartments, but femoral muscle mass is the major compartment associated with physical function in older adults.

Effects of eccentric treadmill exercise on inflammatory gene expression in human skeletal muscle.

The present study examined the skeletal muscle expression of several genes related to the inflammatory process before and after a bout of downhill running. Twenty-nine males between the ages of 18 and 35 years performed a 45-min downhill (-17.5%) treadmill protocol at 60% of maximal oxygen consumption. Venous bloods samples and muscle biopsy samples from the vastus lateralis were donated prior to and at 3-h and 24-h postexercise, along with ratings of perceived muscle soreness. Serum creatine kinase (CK) was determined, as was skeletal muscle gene expression of interleukin (IL)-6, IL-8, IL-12 (p35), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, cyclooxygenase 2 (COX2), and nuclear factor kappa B (NFkB) (p105/p50). Gene expression was analyzed using RT-PCR and compared with a standard housekeeping gene (beta-actin). Data were analyzed for statistical differences using multivariate analysis of variance with univariate follow-up. In addition, Pearson correlations were conducted to determine if any significant relationship exists between any of these transcripts and both CK and muscle soreness. Significant (p < 0.05) up-regulations in IL-6, IL-8, and COX2 mRNA expression were observed compared with baseline, whereas no significant changes for IL-12, IL-1beta, TNF-alpha, or NFkB were noted. Significant increases in IL-6 mRNA were observed at 3 h (p < 0.001) and 24 h (p = 0.043), whereas significant increases in IL-8 (p = 0.001) and COX2 (p = 0.046) mRNA were observed at 3-h postexercise. In addition, muscle soreness was significantly correlated with IL-8 at 24 h (r = -0.370; p = 0.048), whereas CK was significantly related to NFkB at baseline (r = -0.460; p = 0.012). These data indicate that increases in the mRNA expression of IL-6, IL-8, and COX2 occur in the vastus lateralis as a result of damaging eccentric exercise in young, recreationally trained males. Further, it appears that IL-8 transcription may play some role in inhibiting postexercise muscle soreness, possibly through regulation of angiogenesis.

Skeletal muscle apoptotic signaling predicts thigh muscle volume and gait speed in community-dwelling older persons: an exploratory study.

Background Preclinical studies strongly suggest that accelerated apoptosis in skeletal myocytes may be involved in the pathogenesis of sarcopenia. However, evidence in humans is sparse. In the present study, we investigated whether apoptotic signaling in the skeletal muscle was associated with indices of muscle mass and function in older persons. Methodology/Principal Findings Community-dwelling older adults were categorized into high-functioning (HF) or low-functioning (LF) groups according to their short physical performance battery (SPPB) summary score. Participants underwent an isokinetic knee extensor strength test and 3-dimensional magnetic resonance imaging of the thigh. Vastus lateralis muscle samples were obtained by percutaneous needle biopsy and assayed for the expression of a set of apoptotic signaling proteins. Age, sex, number of comorbid conditions and medications as well as knee extensor strength were not different between groups. HF participants displayed greater thigh muscle volume compared with LF persons. Multivariate partial least squares (PLS) regressions showed significant correlations between caspase-dependent apoptotic signaling proteins and the muscular percentage of thigh volume (R2 = 0.78; Q2 = 0.61) as well as gait speed (R2 = 0.81; Q2 = 0.56). Significant variables in the PLS model of percent muscle volume were active caspase-8, cleaved caspase-3, cytosolic cytochrome c and mitochondrial Bak. The regression model of gait speed was mainly described by cleaved caspase-3 and mitochondrial Bax and Bak. PLS predictive apoptotic variables did not differ between functional groups. No correlation was determined between apoptotic signaling proteins and muscle strength or quality (strength per unit volume). Conclusions/Significance Data from this exploratory study show for the first time that apoptotic signaling is correlated with indices of muscle mass and function in a cohort of community-dwelling older persons. Future larger-scale studies are needed to corroborate these preliminary findings and determine if down-regulation of apoptotic signaling in skeletal myocytes will provide improvements in the muscle mass and functional status of older persons.