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Abstracts
Muscle sarcopenia: an overview. Mishra SK, Misra V. Department of Neurology, Keck School of Medicine, University of Southern California, 1975 Zonal Avenue KAM 410, Los Angeles, CA 90033, USA. Smishra@hsc.usc.edu Sarcopenia is the physiological age related decline in muscle mass and strength. The aetiology is multifactorial involving changes in muscle metabolism, endocrine changes, nutritional factors and mitochondrial & genetic factors. Various treatment modalities have been utilized including hormone replacement therapies but only high resistance training (HIRT) exercise has been of significant benefit. Despite recent advances the exact pathogenesis and therapies are not well understood and need further investigation. This paper reviews the current knowledge of aetiopathogenesis and treatments of sarcopenia and suggests future strategies to enhance the understanding of muscle aging and potential therapies. PMID: 14959562 [PubMed - in process]
Muscle changes in aging. Basu R, Basu A, Nair KS. K. Sreekumaran Nair, MD, PhD, Mayo Clinic Foundation200 1st Street SW, Rm 5-194, Rochester, MN 55905, U.S.A. Phone: 507-255-6515. Fax: 507-255-4828. E-mail: nair.sree@mayo.edu This review summarizes the recent studies to understand the mechanisms of sarcopenia of aging. A decrease in mitochondrial and nuclear gene transcriptions in skeletal muscle is likely to be responsible for reduced synthesis rates of muscle mitochondrial protein, myosin heavy chain (MHC) and actin. A decrease in muscle mitochondrial protein synthesis could contribute to reduced mitochondrial function. A decrease in synthesis rate of MHC and actin, the key contractile proteins could be responsible for reduced muscle strength. The MHC synthesis rate seems to result from a selective decrease in transcription of MHC isoforms (MHCIIa and IIx) responsible for fast-twitch fibers. Resistance training increases MHC-I isoform mRNA levels with an overall increase in MHC synthesis rate. Aerobic training increases muscle oxidative enzymes equally in young and old but its impact on overall mitochondrial function remains to be clearly defined. Long-term studies are needed to determine the potential benefits and undesirable effects of replacements of various hormones that decline with aging. An individualized exercise prescription involving both aerobic and resistance training is definitely helpful to overcome many aging-related muscle dysfunctions. PMID: 12474025 [PubMed - in process]
Managing sarcopenia with progressive resistance exercise training. Yarasheski KE. Kevin E.Yarasheski, PhD, Washington University Medical School, Division of Metabolism, Endocrinology and Diabetes, 660 South Euclid Avenue BOX 8127, St. Louis, MO 63110. Ph# 314-362-8173. FAX# 314-362-8188. e-mail:key@im.wustl.edu Advancing age appears to alter the chemical and physical properties of skeletal muscle proteins. Alterations include: reduced contractile, mitochondrial, and enzyme protein synthesis rates, altered expression and post-translational modifications to muscle proteins, reduced maximum voluntary muscle strength, reduced muscle strength per unit muscle mass and muscle power. These age-associated impairments in muscle protein quantity and quality contribute to physical disability and frailty, a loss of independent function, the risk of falling and fractures, and contribute to escalating health care costs. Progressive resistance exercise training is a potent, non-pharmacologic, effective therapy that opposes the impairments in muscle protein quantity and quality in middle age and physically frail adults. In the absence of contraindications to exercise, muscle proteins adapt to an exercise training stimulus despite the depredation of age. The proposed pathogenesis for some of these impairments is briefly reviewed. Evidence that supports the use of progressive resistance exercise training to restore muscle quality and quantity in elderly adults is reviewed. PMID: 12474027 [PubMed - in process]
Sarcopenia--a critical perspective. Hepple RT. Faculty of Kinesiology and Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. hepple@ucalgary.ca Aging is associated with a progressive decline in skeletal muscle mass and function (sarocopenia). Despite several years of research, controversy exists regarding the manifestations and causes of sarcopenia. In the former respect, whereas a preferential loss of so-called "fast-twitch" muscle fibers occurs in rat models of aging, this appears unlikely in human skeletal muscle. In the latter respect, whereas a decline in physical activity with aging contributes to whole-muscle atrophy, it cannot explain the marked heterogeneity in muscle fiber size seen in aged muscles. Similarly, systemic alterations, such as reduced blood levels of anabolic hormones and nutritional deficits, although involved in modulating the degree of whole-muscle atrophy, cannot explain the observation that only some fibers atrophy and die while most appear unaffected. A further significant question remaining is that if death of some muscle fibers is normal and perhaps advantageous (that is, by removing malfunctioning cells), what is the capacity for muscle fiber regeneration in adult skeletal muscle and can this process be augmented in aging muscles? Publication Types:
Serum myostatin-immunoreactive protein is increased in 60-92 year old women and men with muscle wasting. Yarasheski KE, Bhasin S, Sinha-Hikim I, Pak-Loduca J, Gonzalez-Cadavid NF. Kevin E.Yarasheski, PhD, Washington University Medical School, Division of Metabolism, Endocrinology and Diabetes, 660 South Euclid Avenue BOX 8127, St. Louis, MO 63110. Ph# 314-362-8173. FAX# 314-362-8188. e-mail:key@im.wustl.edu BACKGROUND: Myostatin is a recently discovered member of the TGF-b superfamily of genes. It is expressed in skeletal muscle and believed to suppress muscle growth. Myostatin-null mice develop skeletal muscles that are 2-3x larger than wild type mice. Serum and intramuscular concentrations of myostatin-immunoreactive protein are increased in AIDS-muscle wasting and are inversely related with fat-free mass (FFM). OBJECTIVE: We hypothesized that increased expression of the myostatin gene is associated with the reduction in FFM and muscle mass typical of advancing age. DESIGN: A cross-sectional comparison of serum myostatin-immunoreactive protein levels, FFM and skeletal muscle mass in 19-35 yr old men and women (young), healthy 60-75 yr old men and women (middle-aged), and physically frail 76-92 yr old women. RESULTS: Muscle mass declined with advancing age in both men and women. Serum myostatin-immunoreactive protein levels were the highest in the 76-92 yr old women (P<0.05). Middle-aged men and women had higher serum myostatin levels than young men and women (P<0.05). FFM and muscle mass, corrected for height, were inversely correlated with serum myostatin-immunoreactive protein concentrations. CONCLUSIONS: These findings suggest that serum myostatin may be a biomarker of age-associated sarcopenia. They are consistent with the hypothesis that the human myostatin gene product is a suppressor of skeletal muscle growth in advancing age. PMID: 12474026 [PubMed - in process]
Mitochondrial DNA mutations as a fundamental mechanism in physiological declines associated with aging. Pak JW, Herbst A, Bua E, Gokey N, McKenzie D, Aiken JM. Department of Animal Health and Biomedical Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA. The hypothesis that mitochondrial DNA damage accumulates and contributes to aging was proposed decades ago. Only recently have technological advancements, which facilitate microanalysis of single cells or portions of cells, revealed that mtDNA deletion mutations and, perhaps, single nucleotide mutations accumulate to physiologically relevant levels in the tissues of various species with age. Although a link between single nucleotide mutations and physiological consequences in aging tissue has not been established, the accumulation of deletion mutations in skeletal muscle fibres has been associated with sarcopenia. Different, and apparently random, deletion mutations are specific to individual fibres. However, the mtDNA deletion mutation within a phenotypically abnormal region of a fibre is the same, suggesting a selection, amplification and clonal expansion of the initial deletion mutation. mtDNA deletion mutations within a muscle fibre are associated with specific electron transport system abnormalities, muscle fibre atrophy and fibre breakage. These data point to a causal relationship between mitochondrial DNA mutations and the age-related loss of muscle mass. PMID: 12882328 [PubMed - indexed for MEDLINE]
The contribution of reactive oxygen species to sarcopenia and muscle ageing. Fulle S, Protasi F, Di Tano G, Pietrangelo T, Beltramin A, Boncompagni S, Vecchiet L, Fano G. Istituto Interuniversitario di Miologia, Universita Degli Studi G. d'Annunzio, Nuovo Polo Didattico Pal. B, Via dei Vestini 29, Chieti I-66013, Italy. Ageing is a complex process that in muscle in usually associated with a decrease in mass, strength, and velocity of contraction. One of the most striking effects of ageing on muscle is known as sarcopenia, a process that is the result of many cellular changes, such as a reduction in the number of motor units coupled with an increase in motor unit size, progressive denervation, decreased synthesis of myofibrillar components, atrophy due to disuse, accumulation of connective tissue, etc. It has been suggested that sarcopenia may be triggered by reactive oxygen species (ROS) that have accumulated throughout one's lifetime. ROS, which are generated by the addition of a single electron to the oxygen molecule, are formed in all tissues including muscle fibres and, especially, in the mitochondrial respiratory chain. Such reactive elements are usually quite harmful and result in oxidative stress that can damage other cellular components such as DNA, proteins, lipids, etc. resulting in further damage to the cells and tissues. As a consequence, the intra and intercellular membranes of the muscle fibers, in particular those of the Sarcoplasmic reticulum, may be modified and the Ca(2+) transport mechanism altered. During the ageing process ROS production may drastically increase because of an altered function of the respiratory chain and an insufficient functioning of the antioxidant cellular defences. How such an oxidative insult plays a role in the age-related decrease of muscle performance and mass has yet to be defined. What does have a clear role in the progression of sarcopenia is the significant reduction of the regenerative potential of muscle fibres. This reduction is due to a reduced pool of satellite cells that are usually recruited to replace damaged fibres and promote their regeneration. Exercise as a method to prevent or at least delay sarcopenia has been discussed in many scientific reports. While on the one hand, it seems clear that exercise is effective in reducing the loss of muscle mass, on the other it appears that physical activity increases both the mechanical damage and the accumulation of free radicals as a result of an increase in the aerobic metabolism of the muscles involved. PMID: 14724060 [PubMed - indexed for MEDLINE]
Musculoskeletal aging. Leveille SG. Research and Training Institute, Hebrew Rehabilitation Center for Aged, Boston, MA 02131, USA. leveille@mail.hrca.harvard.edu PURPOSE OF REVIEW: Chronic conditions associated with musculoskeletal aging contribute to a heavy functional and economic burden for our rapidly aging population. The purpose of this article is to review recent investigations in musculoskeletal epidemiology related to aging. RECENT FINDINGS: Well over half the older adults in the United States report chronic joint symptoms. With the projected growth of the older population in the next 25 years, the number of elders with arthritis is expected to double to 41 million. Accumulating evidence points to large ethnic and racial differences in the prevalence of arthritis. Primary care interventions to improve self-management of arthritis have been developed and tested, although further work in this area is warranted. Progress is being made in other major chronic conditions associated with aging. Research shows that optimal screening for osteoporotic fracture risk will require risk factor information in addition to bone densitometry. Recent findings shed new light on treatments for osteoporosis and musculoskeletal pain. A new field of study is investigating sarcopenia, or skeletal muscle loss, in very old populations. Research to date has uncovered evidence that this disabling condition may be the result of immunologic and hormonal changes related to aging. SUMMARY: Investigations in many areas are contributing to a better understanding of the major chronic conditions that affect the lives of many older adults. However, the surge in the elderly population will require far greater research and intervention efforts to postpone or prevent a huge population burden of disability related to common musculoskeletal problems of old age. PMID: 14770095 [PubMed - in process]
Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy. Sorensen MB, Rosenfalck AM, Hojgaard L, Ottesen B. Department of Obstetrics and Gynecology, Hvidovre Hospital, University of Copenhagen, Denmark. m.sorensen@rbh.nthames.nhs.uk OBJECTIVE: Menopause is linked to an increase in fat mass and a decrease in lean mass exceeding age-related changes, possibly related to reduced output of ovarian steroids. In this study we examined the effect of combined postmenopausal hormone replacement therapy (HRT) on the total and regional distribution of fat and lean body mass. RESEARCH METHODS AND PROCEDURES: Sixteen healthy postmenopausal women (age: 55 +/- 3 years) were studied in a placebo-controlled, crossover study and were randomized to 17beta estradiol plus cyclic norethisterone acetate (HRT) or placebo in two 12-week periods separated by a 3-month washout. Total and regional body composition was measured by DXA at baseline and in the 10th treatment week in both periods. Changes were compared by a paired Student's t test. RESULTS: The change in body weight during HRT was equal to the change during placebo (-24.6 g vs. -164 g, p = 0.42), but relative fat mass was significantly reduced (-0.5% vs. +1.24%, p < 0.01). During HRT, compared with during placebo, lean body mass increased (+347 g vs. -996 g, p < 0.01) and total fat mass decreased (-400 g vs. +836 g, p = 0.06). Total bone mineral content increased (+28.9 g vs. -4.4 g, p = 0.04) and abdominal fat decreased (-185 g vs. +253 g, p = 0.04) during HRT compared with placebo. DISCUSSION: HRT is linked to the reversal of both menopause-related obesity and loss of lean mass, without overall change in body weight. The increase in lean body mass during HRT is likely explained by muscle anabolism, which in turn, prevents disease in the elderly. Publication Types:
Exercise treatment to counteract protein wasting of chronic diseases. Zinna EM, Yarasheski KE. Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. PURPOSE OF REVIEW: The objective is to summarize the findings from recent (June 2001-2002) studies that have examined the potential benefits of exercise training for the treatment of wasting associated with sarcopenia, cancer, chronic renal insufficiency, rheumatoid arthritis, osteoarthritis and HIV. In many clinical conditions, protein wasting and unintentional weight loss are predictors of morbidity and mortality. The pathogenesis of protein wasting in these conditions can be different, but the fundamental mechanism is an imbalance between muscle protein synthetic and proteolytic processes. The muscle proteins most affected and the precise alterations in their synthetic and proteolytic rates that occur in each cachectic condition are still under investigation. RECENT FINDINGS: Regular exercise, or sometimes just a modest increase in physical activity, can mitigate muscle protein wasting. Aerobic exercise training primarily alters mitochondrial and cytosolic proteins (enzyme activities), while progressive resistance exercise training predominantly increases contractile protein mass. Previous studies indicate that resistance exercise acutely increases the muscle protein synthetic rate more than muscle proteolysis such that the muscle amino acid balance is increased for up to 2 days after exercise. Progressive resistance exercise training increases muscle protein synthesis and muscle mass, but attenuates the increment in proteolysis that results from a single bout of resistance exercise. The cellular mechanisms that produce these adaptations are not entirely clear. SUMMARY: In general, patients with wasting conditions who can and will comply with a proper exercise program gain muscle protein mass, strength and endurance, and, in some cases, are more capable of performing the activities of daily living. Publication Types:
Strength training in older women: early and late changes in whole muscle and single cells. Frontera WR, Hughes VA, Krivickas LS, Kim SK, Foldvari M, Roubenoff R. Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA. frontera.walter@mgh.harvard.edu In order to examine the relative contribution of neural- and muscle-based adaptation to strength training, we studied early (2 weeks) and later (12 weeks) effects of strength training on muscle size and strength and type I single-fiber size and contractility in 14 elderly women (aged 68-79 years) and seven young controls. Older subjects were randomized to training (n = 7) or control (n = 7) groups. Strength did not change, but whole muscle size increased significantly after 2 weeks. After 12 weeks, strength, whole muscle size, and specific force all increased. No changes occurred in the control group. In single fibers, no changes in size and contractility were noted after 2 weeks, but specific force was higher in the training group after 12 weeks. Early adaptations to strength training in elderly women cannot be attributed to changes at the cellular level and therefore occur primarily in the central nervous system. Later, cellular adaptations in specific force track closely whole muscle changes. Publication Types:
Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: the Framingham Heart Study. Payette H, Roubenoff R, Jacques PF, Dinarello CA, Wilson PW, Abad LW, Harris T. Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Tufts University, Boston, Massachusetts, USA. helene.payette@usherbrooke.ca OBJECTIVES: To assess the prognostic role of the inflammatory cytokine, interleukin 6 (IL-6), and insulin-like growth factor-1 (IGF-1) in predicting 2-year changes in fat-free mass (FFM) while controlling for potential confounders. DESIGN: Population-based cohort, the Framingham Heart Study, examined in 1992-93 and 1994-95. SETTING: General community. PARTICIPANTS: Two hundred thirty-two men and 326 women aged 72 to 92. MEASUREMENTS: IGF-1 was measured using radio-immunoassay and cellular IL-6 production using non-cross-reacting radioimmunoassays. FFM was estimated using population-specific equations for predicting FFM from bioelectrical impedance analysis developed separately for men and women. RESULTS: Higher IGF-1 predicted smaller loss of FFM in men than lower IGF-1 did (P=.002), after adjusting for age, baseline FFM, fat mass, and 2-year weight changes, whereas cellular IL-6 was a significant predictor of sarcopenia in women (P=.02). Weight change was a strong determinant of change in FFM in both sexes (P<.0001). CONCLUSION: Predictors of sarcopenia include body composition characteristics that are common to men and women and sex-specific metabolic predictors. Sarcopenia appears to reflect a withdrawal of anabolic stimuli, such as growth hormone, in men but an increase in catabolic stimuli, such as cellular IL-6, in women. PMID: 12919235 [PubMed - indexed for MEDLINE]
Persistent expression of the alpha1S-dihydropyridine receptor in aged human skeletal muscle: implications for the excitation-contraction uncoupling hypothesis of sarcopenia. Ryan M, Butler-Browne G, Erzen I, Mouly V, Thornell LE, Wernig A, Ohlendieck K. Department of Pharmacology, University College Dublin, Belfield, Dublin 4, Ireland. Previous studies on aged animal muscle suggest that excitation-contraction uncoupling and fibre transitions play a central role in sarcopenia, the progressive loss and functional decline of aging skeletal muscle fibres. A drastic reduction in the voltage-sensing alpha1S-subunit of the transverse-tubular dihydropyridine receptor is believed to be the underlying cause for a decreased transmission of the surface depolarization signal into Ca2+-mediated muscle contraction. Extending these studies to human muscle, we asked whether potential changes in the relative expression of the voltage sensor occur in senescent human fibres. For internal standardization and as markers of potential fast-to-slow transitions, the fast isoforms of the Ca2+-binding element calsequestrin and the myosin heavy chain were employed. Besides small inter-individual variations in expression levels, the microsomal immunoblot analysis of vastus lateralis autopsy specimens from male humans aged 18 to 82 years of age showed no major changes in the relative abundance of the alpha1S- and alpha2-dihydropyridine receptor, fast calsequestrin and the slow/fast myosin heavy chains. The oligomeric status of the alpha1S-dihydropyridine receptor was unaltered in aged fibres. Biochemical assays revealed no significant modifications in Ca2+-ATPase activity and a reduced Ca2+-binding capacity in aged human muscle preparations. Although impairments of other Ca2+-regulatory proteins and/or disturbed protein-protein interactions might be involved in the pathophysiological changes of sarcopenia, dihydropyridine receptor and calsequestrin expression seem to be preserved during the aging process of human skeletal muscle fibres. Hence, the supposition that excitation-contraction uncoupling is responsible for sarcopenia can not be transferred from animal models to senescent human muscle without modifications. PMID: 12632093 [PubMed - indexed for MEDLINE]
The molecular responses of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats. Chakravarthy MV, Booth FW, Spangenburg EE. Department of Integrative Biology, University of Texas Medical School, Houston 77030, USA. Approximately 50% of humans older than 85 years have physical frailty due to weak skeletal muscles. This indicates a need for determining mechanisms to combat this problem. A critical cellular factor for postnatal muscle growth is a population of myogenic precursor cells called satellite cells. Given the complex process of sarcopenia, it has been postulated that, at some point in this process, a limited satellite cell proliferation potential could become rate-limiting to the regrowth of old muscles. It is conceivable that if satellite cell proliferative capacity can be maintained or enhanced with advanced age, sarcopenia could potentially be delayed or prevented. Therefore, the purposes of this paper are to describe whether IGF-I can prevent muscular atrophy induced by repeated cycles of hindlimb immobilization, increase the in vitro proliferation in satellite cells from these muscles and, if so, the molecular mechanisms by which IGF-I mediates this increased proliferation. Our results provide evidence that IGF-I can enhance aged muscle regrowth possibly through increased satellite cell proliferation. The results also suggest that IGF-I enhances satellite cell proliferation by decreasing the cell cycle inhibitor, p27Kip1, through the PI3'-K/Akt pathway. These data provide molecular evidence for IGF-I's rescue effect upon aging-associated skeletal muscle atrophy. PMID: 11915927 [PubMed - indexed for MEDLINE]
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