Sarcopenia & Testosterone (Beyond Hypogonadism)

[Michael Scally MD]

Re: The Brave New World of Function-Promoting Anabolic Therapies

The evaluation of physical function is still not considered as relevant as that of other clinical or biochemical parameters. Gait speed has repeatedly and increasingly been proposed as a unique measure of physical performance and as a potential screening tool, but adoption has remained inconsistent. The study by Studenski et al fills an important research gap and paves the way to a broader adoption of gait speed assessment. Their findings from a pooled analysis of 9 major cohort studies confirm gait speed as a predictor of mortality in older persons and also provide the statistical foundations to estimate expected survival at different ages based only on gait speed. If one reads the SARM studies, the current use is on this very testing.


Studenski S, Perera S, Patel K, et al. Gait Speed and Survival in Older Adults. JAMA: The Journal of the American Medical Association 2011;305(1):50-8. Gait Speed and Survival in Older Adults, January 5, 2011, Studenski et al. 305 (1): 50 — JAMA

Context - Survival estimates help individualize goals of care for geriatric patients, but life tables fail to account for the great variability in survival. Physical performance measures, such as gait speed, might help account for variability, allowing clinicians to make more individualized estimates.

Objective - To evaluate the relationship between gait speed and survival.

Design, Setting, and Participants - Pooled analysis of 9 cohort studies (collected between 1986 and 2000), using individual data from 34 485 community-dwelling older adults aged 65 years or older with baseline gait speed data, followed up for 6 to 21 years. Participants were a mean (SD) age of 73.5 (5.9) years; 59.6%, women; and 79.8%, white; and had a mean (SD) gait speed of 0.92 (0.27) m/s.

Main Outcome Measures - Survival rates and life expectancy.

Results - There were 17 528 deaths; the overall 5-year survival rate was 84.8% (confidence interval [CI], 79.6%-88.8%) and 10-year survival rate was 59.7% (95% CI, 46.5%-70.6%). Gait speed was associated with survival in all studies (pooled hazard ratio per 0.1 m/s, 0.88; 95% CI, 0.87-0.90; P < .001). Survival increased across the full range of gait speeds, with significant increments per 0.1 m/s. At age 75, predicted 10-year survival across the range of gait speeds ranged from 19% to 87% in men and from 35% to 91% in women. Predicted survival based on age, sex, and gait speed was as accurate as predicted based on age, sex, use of mobility aids, and self-reported function or as age, sex, chronic conditions, smoking history, blood pressure, body mass index, and hospitalization.

Conclusion - In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults.


Also see accompanying commentary: Cesari M. Role of Gait Speed in the Assessment of Older Patients. JAMA: The Journal of the American Medical Association 2011;305(1):93-4. Role of Gait Speed in the Assessment of Older Patients, January 5, 2011, Cesari 305 (1): 93 — JAMA

Or news report: Walking Speed and Survival Connected - http://www.medpagetoday.com/Geriatrics/GeneralGeriatrics/24180

 

[Michael Scally MD]

Smith GI, Atherton P, Reeds DN, et al. Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial. Am J Clin Nutr. Dietary omega-3 fatty acid supplementation increas... [Am J Clin Nutr. 2010] - PubMed result

BACKGROUND: Loss of muscle mass with aging is a major public health concern. Omega-3 (n-3) fatty acids stimulate protein anabolism in animals and might therefore be useful for the treatment of sarcopenia. However, the effect of omega-3 fatty acids on human protein metabolism is unknown.

OBJECTIVE: The objective of this study was to evaluate the effect of omega-3 fatty acid supplementation on the rate of muscle protein synthesis in older adults.

DESIGN: Sixteen healthy, older adults were randomly assigned to receive either omega-3 fatty acids or corn oil for 8 wk. The rate of muscle protein synthesis and the phosphorylation of key elements of the anabolic signaling pathway were evaluated before and after supplementation during basal, postabsorptive conditions and during a hyperaminoacidemic-hyperinsulinemic clamp.

RESULTS: Corn oil supplementation had no effect on the muscle protein synthesis rate and the extent of anabolic signaling element phosphorylation in muscle. Omega-3 fatty acid supplementation had no effect on the basal rate of muscle protein synthesis (mean +/- SEM: 0.051 +/- 0.005 compared with 0.053 +/- 0.008%/h before and after supplementation, respectively; P = 0.80) but augmented the hyperaminoacidemia-hyperinsulinemia-induced increase in the rate of muscle protein synthesis (from 0.009 +/- 0.005%/h above basal values to 0.031 +/- 0.003%/h above basal values; P < 0.01), which was accompanied by greater increases in muscle mTOR(Ser2448) (P = 0.08) and p70s6k(Thr389) (P < 0.01) phosphorylation.

CONCLUSION: Omega-3 fatty acids stimulate muscle protein synthesis in older adults and may be useful for the prevention and treatment of sarcopenia.

This trial was registered at clinical trials.gov as NCT00794079.

 

[BBC3]

I just would like to further interject a though (on my way out the door). In terms of apoctosis, I was having a discussion the other day with regard to cancer and treatments thereof. Apoctosis is a normal function that serves as "self-defense" in many scenarios. For example, one of the body's responses to certain types of cancer (and other things) is apoctosis, the INTENTIONAL self destruction of cells neighboring an impropery growth phenomena, hence to isolate and prevent the spread.

I wonder how much apoctosis occurs with relation to fatty tumors.?? I have always suspected they are some kind of protective response, or even a "resvoir" if you will, designed to hold bad stuff in isolation?? Any thoughts there doc?

Sorry, not to appear hi-jacking. So the whole point is that a systemwide prevention of the natural process would not work. It brings to light questions with regard to AAS and GH application specifically..

 

[Michael Scally MD]

The effectiveness of resistance Exercise (RE) for strength improvement among aging persons is inconsistent across investigations. While much research has investigated strength increases accompanying single-cohort interventions, most have examined only one or two training programs, providing only a glimpse of the overall dose–response relationship. Debate concerning the appropriateness of RE among older individuals has been cultivated by questions of the general efficacy and safety for this population.

There are very few published accounts that have examined the overall benefit of RE for strength in aging persons while considering a continuum of dosage schemes, treatment durations, and/or age ranges on longitudinal strength adaptation. As a result, it is difficult to evaluate the treatment effects coinciding with these factors. Further, although the existing body of evidence regarding the utility of resistance exercise for strength improvements among older adults has recently been deemed to be supported by the highest category of evidence (i.e. “Evidence Category A.”), a systematic review to assess treatment effects across multiple strength measures, and potential moderating variables more generalizable to RE prescription, is yet to be completed. To date, the most comprehensive reviews related to this topic have either limited the analysis of strength to a single measure (i.e. knee extension), or have compared multimodal exercise regiments for general changes in overall functional capacity, not specific to strength outcomes.

The purposes of this review and meta-analyses were to examine the effects of resistance exercise among older adults for multiple upper- and lower-body strength outcomes, and across multiple dosing schemes.


Peterson MD, Rhea MR, Sen A, Gordon PM. Resistance exercise for muscular strength in older adults: a meta-analysis. Ageing Res Rev 2010;9(3):226-37. Resistance exercise for muscular strength in older... [Ageing Res Rev. 2010] - PubMed result

PURPOSE: The effectiveness of resistance exercise for strength improvement among aging persons is inconsistent across investigations, and there is a lack of research synthesis for multiple strength outcomes.

METHODS: The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. A meta-analysis was conducted to determine the effect of resistance exercise (RE) for multiple strength outcomes in aging adults. Randomized-controlled trials and randomized or non-randomized studies among adults > or = 50 years, were included. Data were pooled using random-effect models. Outcomes for 4 common strength tests were analyzed for main effects. Heterogeneity between studies was assessed using the Cochran Q and I(2) statistics, and publication bias was evaluated through physical inspection of funnel plots as well as formal rank-correlation statistics. A linear mixed model regression was incorporated to examine differences between outcomes, as well as potential study-level predictor variables.

RESULTS: Forty-seven studies were included, representing 1079 participants. A positive effect for each of the strength outcomes was determined however there was heterogeneity between studies. Regression revealed that higher intensity training was associated with greater improvement. Strength increases ranged from 9.8 to 31.6 kg, and percent changes were 29+/-2, 24+/-2, 33+/-3, and 25+/-2, respectively for leg press, chest press, knee extension, and lat pull.

CONCLUSIONS: RE is effective for improving strength among older adults, particularly with higher intensity training. Findings therefore suggest that RE may be considered a viable strategy to prevent generalized muscular weakness associated with aging.

 

[Michael Scally MD]

The importance of subjects’ points of view on their health status and use of health care is widely recognized. Patient reported outcomes (PROs) provide subjects’ perspectives on impacts of a disease and therapies used to treat it. Existing measures (eg, Subclinical Status in Functional Limitation and Disability, World Health Organization Disability Assessment Schedule II) evaluate functional assessment and limitations but are not specific to muscle loss. A PRO measure covering loss in muscle strength specific to sarcopenia would complement objective measures while assessing areas (eg, household activities, endurance) individuals feel are important.

There are a limited number of relevant disease-specific measures applicable to a population with sarcopenia; however, most assess specific aspects, such as dementia, depression, and urological problems. Generic measures relevant to this population, such as the Instrumental Activities of Daily Living Scale, were developed solely from clinician input and lack specific relevance to sarcopenia. A review of existing literature yielded no readily available, psychometrically sound measure to capture PROs associated with loss of muscle strength in sarcopenia. This study aimed to address this gap by developing a measure that assesses the burden of muscle loss in sarcopenia.


Evans CJ, Chiou CF, Fitzgerald KA, et al. Development of a new patient-reported outcome measure in sarcopenia. J Am Med Dir Assoc 2011;12(3):226-33. Development of a new patient-reported outcome meas... [J Am Med Dir Assoc. 2011] - PubMed result

OBJECTIVE: The objective of this study was to develop a patient-reported outcome (PRO) to assess reduced muscle strength in sarcopenia.

DESIGN: Qualitative research study.

SETTING: University of Arkansas for Medical Sciences.

PARTICIPANTS: Subjects with sarcopenia.

MEASUREMENTS: Adults aged 55 years and older with sarcopenia (n = 12) attended open-ended, concept elicitation interviews to characterize the functional effects of reduced muscle strength on their lives. The resulting qualitative data were analyzed using a qualitative analysis software program (Atlas.ti [Atlas.ti GmbH, Berlin, Germany]) and a common set of codes was developed to summarize the data. Subsequently, the initial PRO measure was drafted. Cognitive interviews were then conducted with additional sarcopenia subjects (n = 12) to refine the measure.

RESULTS: Qualitative interviews identified key concepts (eg, impacts) in the areas of activities of daily living, emotions, social activities, energy, balance, coordination, sleep, and strength. Based on data from the cognitive debriefing interviews (eg, understandability, relevance, suggestions to reword items), the PRO measure development team came to consensus on which items or parts of the instructions to retain, revise, or delete. The final measure included 14 items.

CONCLUSION: The final PRO measure, the Age-Related Muscle Loss Questionnaire, can be used in both clinical practice and clinical trial settings to assess functional impacts of reduced muscle strength in sarcopenia.

 

[Michael Scally MD]

Sarcopenia =/= Dynapenia

THE loss of muscle mass with age has long been anecdotally recognized as Shakespeare eloquently pointed out nearly a half millennium ago in his monologue The Seven Ages of Man when he wrote:

‘‘. . .The sixth age shifts into the lean and slipper’d pantaloon,
With spectacles on nose and pouch on side;
His youthful hose, well sav’d, a world too wide,
For his shrunk shank. . .’’

In 1989 this observation was brought to the forefront of science when Dr. Irwin Rosenberg wrote: ‘‘No decline with age is more dramatic or potentially more functionally significant than the decline in lean body mass. . . Why have we not given it more attention? Perhaps it needs a name derived from the Greek. I’ll suggest a couple: sarcomalacia or sarcopenia’.’ These thoughts ignited a frenzy of research to determine what caused this age-related loss of lean mass and its functional consequences. The proposed term sarcopenia (translated as ‘‘poverty of flesh’’) stuck, and was originally defined as the age-related loss in muscle mass. However, over the past decade sarcopenia has become a catch-all term that is now regularly defined as the age related loss of skeletal muscle mass and strength, with even the National Institute on Aging public health service documents now referring to sarcopenia in this manner.

The linking of changes in muscle mass AND strength (defined here as the maximal force or power produced voluntarily) via the same word (sarcopenia) implies that these are causally linked and that changes in skeletal muscle mass are directly and fully responsible for changes in strength. In this Green Banana article, researchers argue that there is abundant evidence indicating other factors that function to regulate strength simply beyond muscle mass. Thus, linking these two outcomes has resulted in a disproportionately larger research emphasis on the mechanisms of muscle mass change rather than the mechanisms regulating strength. The recent observation that strength greatly reduces the association between muscle mass and functional decline and early death to a statistically nonsignificant level suggests that the contribution of muscle mass on certain outcomes may be primarily due to its association with strength. Thus, it is imperative that a greater understanding of the mechanisms of age-associated losses in strength be developed. Therefore, to encourage research endeavors focusing on understanding the mechanisms of strength, they propose changes in the nomenclature that distinctly separates the age-associated changes in muscle mass and strength.

They suggest that sarcopenia be limited to its original definition of an age-related loss in skeletal muscle mass, and that the term ‘‘dynapenia’’ be applied to describe the age related loss of strength. They feel that this Greek term is appropriate as it translates to ‘‘poverty of strength,’’ which is consistent with other words used in a similar descriptive manner to define age-related losses (i.e., osteopenia, sarcopenia). In the following paper, they will discuss the current evidence indicating a disassociation between changes in muscle mass and strength, followed by an overview of other physiological factors that regulate changes in strength that may serve to modulate the weakness observed with aging.


Clark BC, Manini TM. Sarcopenia =/= dynapenia. J Gerontol A Biol Sci Med Sci 2008;63(8):829-34. Sarcopenia =/= dynapenia. [J Gerontol A Biol Sci Med Sci. 2008] - PubMed result

Maximal voluntary force (strength) production declines with age and contributes to physical dependence and mortality. Consequently, a great deal of research has focused on identifying strategies to maintain muscle mass during the aging process and elucidating key molecular pathways of atrophy, with the rationale that the loss of strength is primarily a direct result of the age-associated declines in mass (sarcopenia). However, recent evidence questions this relationship and in this Green Banana article we argue the role of sarcopenia in mediating the age-associated loss of strength (which we will coin as dynapenia) does not deserve the attention it has attracted in both the scientific literature and popular press. Rather, we propose that alternative mechanisms underlie dynapenia (i.e., alterations in contractile properties or neurologic function), and urge that greater attention be paid to these variables in determining their role in dynapenia.

 

[Michael Scally MD]

Muscle atrophy is a pathological condition of many diseases, including cancer, diabetes, chronic obstructive pulmonary disease, and AIDS and is an extremely debilitating and life-threatening disorder. Myopathy has also been shown to be a dose-limiting side affect of synthetic glucocorticoid treatment, and is a natural consequence of inactivity and aging (sarcopenia). Cancer cachexia is the progressive muscle wasting developed by many cancer patients. Up to 80% of patients with advanced cancer are affected by cachexia where it is directly responsible for the deaths of 20% of these patients. Furthermore, the patients with cachexia have a lower response to anti-neoplastic treatments and are more sensitive to toxic side-effects. Not only is cachexia a predicator for poor outcome for cancer patients, but also for a number of other chronic diseases. Cancer cachexia is estimated to afflict at least 1.3 million cancer patients in the United States, and by 2015 age-related sarcopenia is estimated to affect over 3% of the world’s population. There are no effective treatments for myopathy, thus muscle atrophy represents an important unmet medical need.

Researchers have discovered a novel MuRF1 inhibitor (P013222) using their proprietary E3 ligase screening platform. This MuRF1 inhibitor was shown to have some selectivity for MuRF1, to inhibit MuRF1 autoubiquitylation activity, and to inhibit ubiquitylation of the MuRF1 substrate myosin heavy chain in vitro. P013222 was also found to be non-cytotoxic and to inhibit myosin heavy chain degradation in a cellular atrophy model. The identification of MuRF1 inhibitors will represent a clear step forward in establishing the proof of concept and feasibility of treating muscle wasting with E3 ligase inhibitors.


Eddins MJ, Marblestone JG, Suresh Kumar KG, et al. Targeting the Ubiquitin E3 Ligase MuRF1 to Inhibit Muscle Atrophy. Cell Biochem Biophys. Targeting the Ubiquitin E3 Ligase MuRF1 to Inhibit... [Cell Biochem Biophys. 2011] - PubMed result

Progressive muscle wasting, also known as myopathy or muscle atrophy is a debilitating and life-threatening disorder. Myopathy is a pathological condition of many diseases including cancer, diabetes, COPD, and AIDS and is a natural consequence of inactivity and aging (sarcopenia). Muscle atrophy occurs when there is a net loss of muscle mass resulting in a change in the balance between protein synthesis and protein degradation. The ubiquitin pathway and specific ubiquitin pathway enzymes have been directly implicated in the progression of atrophy. The ubiquitin E3 ligase Muscle-specific RING Finger E3 ligase (MuRF1) is upregulated and increases protein degradation and muscle wasting in numerous muscle atrophy models. The inhibition of MuRF1 could be a novel mechanism to prevent or reverse muscle wasting associated with various pathologies. We screened a small molecule library for inhibitors to MuRF1 activity and identified P013222, an inhibitor of MuRF1 autoubiquitylation. Further, P013222 was shown to inhibit MuRF1-dependent substrate ubiquitylation, and was active in inhibiting MuRF1 in a cellular atrophy model. Thus MuRF1 can be targeted in a specific manner and produce positive results in cellular atrophy models.

 

[Michael Scally MD]

Activities and Mortality in the Elderly

Although physical activity has been shown to have substantial health benefits and to reduce mortality, few studies have examined its impact on survival beyond age 75. Those including these elderly adults have rarely reported age-stratified results and one of these included only men. The relationship between activities and mortality might differ between elderly adults (?75-year olds) and those who are younger and between men and women. Women on average live longer than men but generally have lower activity levels and engage in different activities. Combining men with women might obscure a relationship between activity and mortality (ie, reduce a positive association between physical activity and longevity). Researchers hypothesized that a protective effect of physical activity might be attenuated in late life and differ between men and women. They therefore explored the association of activity on all-cause mortality in a large cohort (nearly 14,000) of elderly (median = 74 years) men and women with information on many potential confounders and followed for 28 years. Because their sample was large and the age range wide, they were able to look at the effect of activity in several age strata (<70, 70–74, 75–79, and 80+ years) and in both sexes.


Paganini-Hill A, Kawas CH, Corrada MaM. Activities and Mortality in the Elderly: The Leisure World Cohort Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2011;66A(5):559-67. Sign In

Background. Although physical activity has substantial health benefits and reduces mortality, few studies have examined its impact on survival beyond age 75.

Methods. Using the population-based Leisure World Cohort Study, we explored the association of activity on all-cause mortality in older adults (median age at baseline = 74 years). We followed 8,371 women and 4,828 men for 28 years or until death (median = 13 years) and calculated relative risks for various measures of activity at baseline using Cox regression analysis for four age groups (<70, 70–74, 75–79, and 80+ years) in men and women separately.

Results. Time spent in active activities, even ½ hour/day, resulted in significantly lower (15–35%) mortality risks compared with no time in active activities. This reduction was evident in all sex–age groups except the youngest men. Participants who reported spending 6 or more hours/day in other less physically demanding activities also had significantly reduced risks of death of 15–30%. The beneficial effect of activities was observed in both those who did and those who did not cut down their activities due to illness or injury. Neither adjustment for potential confounders, exclusion of the first 5 years of follow-up, nor exclusion of individuals with histories of chronic disease substantially changed the findings.

Conclusions. Participation in leisure-time activities is an important health promoter in aging populations. The association of less physically demanding activities as well as traditional physical activities involving moderate exertion with reduced mortality suggests that the protective effect of engagement in activities is a robust one.

 

[Michael Scally MD]

The Role Of Myostatin In Muscle Wasting

Cachexia is a syndrome occurring at terminal stages of diseases such as cancer, chronic heart failure, chronic kidney failure or AIDS. This syndrome is characterized by loss of body weight as a consequence of pathological changes in different metabolic pathways. It leads to increased morbidity and mortality irrespective of the underlying disease. A major role in the development of cachexia is played by the loss of muscle mass accompanied by the loss of fat. Such muscle hypotrophy is the result of multiple alterations at the molecular level, e.g. the disturbance in the balance between protein degradation and protein synthesis.

Proinflammatory cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor-? (TNF?) were shown to play an important role in the development of muscle wasting. However, there is no established treatment for cachexia based on the regulation of their signaling. Many different peptides have received therapeutic interest over the last decade, including ghrelin, leptin, melanocortins, and growth hormone. In 1997, the role of another extracellular factor in the negative regulation of muscle mass, referred to as myostatin, was discovered. Myostatin upregulation was found in the pathogenesis of cancer, HIV, heart failure associated cachexia and aging. It has become one of the main targets in the investigation of the regulation of muscle mass.

Myostatin, also known as growth/differentiation factor-8 (GDF-8) is a member of tumor growth factor ? (TGF-?) family. This protein is a homodimer with a molecular weight of 25 kDa and a disulfide bond between the monomers at the C-terminal regions. Myostatin circulates in the blood in a latent form with an additional non-covalently bound propeptide at the N-terminus. Proteolytic cleavage of the propeptide by the bone morphogenetic protein (BMP)-1/tolloid family of metalloproteinases is necessary for activation of protein function.

The role of myostatin in skeletal muscle was discovered using the method of gene disruption in mice. Mstn null animals showed significant increase in muscle mass (up to two-fold) and decrease of fat tissue compared to the wild type. Similar effects were observed in the presence of natural mutations of Mstn in cattle, sheep, dogs and humans and upon the inhibition of the protein function in adult mice. At the same time, overexpression of Mstn led to the reduction of muscle mass suggesting myostatin to be a negative regulator of skeletal muscle growth. During embryogenesis, myostatin is exclusively expressed in skeletal muscle to control the differentiation and proliferation of the myoblast, but in adulthood, it is not only restricted to skeletal muscle but also detected in other tissues (e.g. heart, adipose tissue, mammary gland).

Myostatin is a negative regulator of myoblast proliferation and differentiation. Normally it functions to regulate hypertrophy of muscles, but a role in the induction of muscle loss was observed in muscle wasting diseases and cachexia associated with severe illnesses. The mechanism of myostatin signaling is complex and involves the activation of several downstream pathways. Additional studies are required to elucidate the cross talk between the signaling cascades and their regulation. The experiments with myostatin propeptide and antimyostatin antibodies showed a positive effect on regulation of muscle mass in different models of wasting but lacked efficacy in phase I clinical trials. The most promising target in terms of cachexia treatment seems to be the activin type II receptor. The blockade of this receptor led to a significant increase in muscle mass and even its restoration in cancer cachexia. Therefore, targeting myostatin and its receptor represent a promising direction in the development of effective treatments for cachexia and muscle wasting diseases.

Myostatin pathway. Myostatin is synthesized and secreted by muscle cell; it signals through the activin IIB/ALK 4/5 heterodimer to activate different pathways resulting in the decrease in muscle growth and differentiation

Different pathways of myostatin signalling. ? The activation of the process, -| the inhibition of the process, -- -- the presence of intermediate steps either unknown or omitted in the figure.

1 Canonical pathway of Smad activation. Myostatin binds to ActRIIB and induces its assembly with activin type I receptor. Subsequent phosphorylation of Smad2/3 leads to its binding with Smad4 and translocation of the complex to the nucleus where it blocks the transcription of genes responsible for the myogenesis. Smad6 and Smad7 compete for the binding with activin type I receptor. Smad7 can also prevent the formation of the Smad 2/3 and Smad4 complex.

2 MAPK activation. The activation of MAPKs is mediated via myostatin using different pathways: TAK-1/MAPKK for p38 MAPK or Ras/Raf/MEK1 for ERK1/2. It leads to the blockade of genes responsible for myogenesis.

3 Inhibition of Akt signalling. Akt phosphorylation occurs in the response to insulin and IGF-1. In normal case, active Akt induces mTOR signal leading to the protein synthesis; at the same time, it inhibits FoxO by phosphorylation. In the pathological conditions, dephosphorylated Akt does not inhibit FoxO. It leads to the accumulation of FoxO in the nucleus where it binds to the DNA and induces the transcription of E3 ubiquitin ligases MURF-1 and Atrogin-1. Smad3 and Smad4 possibly participate in FoxO signalling


Elkina Y, von Haehling S, Anker SD, Springer J. The role of myostatin in muscle wasting: an overview. J Cachex Sarcopenia Muscle 2011;2(3):143-51. The role of myostatin in muscle wasting: an overview

Myostatin is an extracellular cytokine mostly expressed in skeletal muscles and known to play a crucial role in the negative regulation of muscle mass. Upon the binding to activin type IIB receptor, myostatin can initiate several different signalling cascades resulting in the upregulation of the atrogenes and downregulation of the important for myogenesis genes. Muscle size is regulated via a complex interplay of myostatin signalling with the insulin-like growth factor 1/phosphatidylinositol 3-kinase/Akt pathway responsible for increase in protein synthesis in muscle. Therefore, the regulation of muscle weight is a process in which myostatin plays a central role but the mechanism of its action and signalling cascades are not fully understood. Myostatin upregulation was observed in the pathogenesis of muscle wasting during cachexia associated with different diseases (i.e. cancer, heart failure, HIV). Characterisation of myostatin signalling is therefore a perspective direction in the treatment development for cachexia. The current review covers the present knowledge about myostatin signalling pathways leading to muscle wasting and the state of therapy approaches via the regulation of myostatin and/or its downstream targets in cachexia.

 

[Michael Scally MD]

Myostatin Is Associated With Age Related Human Muscle Stem Cell Dysfunction

There is an abundance of descriptive clinical information characterizing the loss of skeletal muscle and strength with aging (sarcopenia) starting in the fifth decade of life. The progressive nature of age-related muscle wasting leads to an increased incidence of injury and loss of autonomy, resulting in a significant loss in quality of life and increased risk of all-cause mortality. Unfortunately, there is a paucity of information on the specific mechanisms of human muscle aging. Therefore, determining the biological processes underlying age-related muscle loss is imperative to design effective treatment strategies for sarcopenia.

The regulation of muscle growth and maintenance of muscle mass is governed by a unique population of muscle resident stem cells referred to as satellite cells (SC).Notably, an age-related decline in the SC pool size, as well as an impaired response to muscle damage, has been documented as a consequence of aging in mice. This age-related impairment may be due to a dysfunction in the intrinsic properties of aged SCs, hindering propagation through the myogenic program and increasing their susceptibility to undergo apoptosis, as well as decreasing their capacity to repopulate the reserve pool. The aged systemic milieu, as well as the SC niche, have also been implicated in the dysfunction of aged SCs to respond to physiological stimuli.

In humans, the literature on whether the SC pool size is maintained with age is equivocal, with some studies showing a reduced SC pool in older adults and others illustrating no change with age. In recent years, research using animal and cell culture models has implicated myostatin (MSTN) as a potential negative regulator of muscle mass and, importantly, SC activity.

MSTN is a transforming growth factor ? (TGF-?) family member that acts as a negative regulator of skeletal muscle growth. The loss or mutation of the portion of the gene encoding the C-terminal region of MSTN results in muscle mass that is typically 2–3 times larger than wild-type mice, resulting in the “double muscled” phenotype. In humans, there is little work demonstrating a direct relationship between MSTN and muscle wasting; however, there is some evidence to support the role of MSTN in disease-related muscle atrophy. Patients with HIV-associated muscle wasting possess higher serum and intramuscular concentrations of MSTN, suggesting that up-regulation of MSTN contributes to the overall loss of skeletal muscle. In addition, age-related elevations in serum MSTN inversely correlate with muscle mass, suggesting that increased systemic MSTN may be a contributing factor to sarcopenia. The lifelong lack of MSTN (Mstn-/- mouse) appears to reduce the aged phenotype compared to age-matched wild-type controls. However, total muscle mass is still reduced as a consequence of aging in Mstn-/- animals, indicating that elevated systemic MSTN is not the sole mediator of sarcopenia. Notably, the precise role of MSTN in regulating muscle mass remains unknown.

The majority of human research on aging and MSTN has focused on MSTN gene expression, illustrating that MSTN expression is up-regulated compared to younger individuals. However, few aging studies have directly examined MSTN protein levels in aged muscle and to date, no in vivo human studies have assessed the role of MSTN in SC function in the context of aging. In mice, it has been demonstrated that MSTN is capable of up-regulating p21, a cyclin-dependent kinase (Cdk) inhibitor that inhibits the cell cycle. MSTN also suppresses Cdk2 expression and retinoblastoma protein (Rb) phosphorylation, which are critical for cell cycle progression, thus impairing SC proliferation. In addition, MSTN may directly inhibit myogenic regulatory factor (MRF) expression, preventing SC proliferation and differentiation.

Thus, MSTN appears to be up-regulated in aged muscle and may be responsible for some degree of muscle wasting. Therefore, to determine the relevance of MSTN in age-related function of SCs in humans, researchers used a model of acute resistance exercise to induce a myogenic response in younger and older men. For the first time, they have examined MSTN in the context of human aging and how it relates to SC activity in vivo. They hypothesized that elevated muscle and SC MSTN levels would be associated with a blunted SC response in the older men.


McKay BR, Ogborn DI, Bellamy LM, Tarnopolsky MA, Parise G. Myostatin is associated with age-related human muscle stem cell dysfunction. Faseb J http://www.fasebj.org/content/early/2012/03/06/fj.11-198663.abstract

Human aging is accompanied by a progressive loss of muscle mass (sarcopenia). We tested the hypothesis that older males (OMs, 70+/-4 yr, n=9) would have a blunted myogenic response to a physiological stimulus compared to younger controls (21+/-3 yr, n=9). Subjects completed an acute bout of intense unilateral muscle loading. Young healthy males matched for body mass and activity level served as the control group. Muscle biopsies and blood were obtained before and at 3, 24, and 48 h after muscle loading. The muscle stem cell response was analyzed using flow cytometry, immunofluorescent microscopy, and standard protein and mRNA analysis.

OMs had 35% fewer basal stem cells and a type II fiber-specific impairment in stem cell content and proliferation. Myogenic determination factor staining and cell cycle analysis illustrated a severely blunted progression through the myogenic program. Myostatin protein and mRNA were 2-fold higher in OMs. Stem cell-specific myostatin levels were not different at baseline; however, there were 67% more myostatin-positive type II-associated stem cells in OMs at 24 h. These data illustrate an age-related impairment of stem cell function in a fiber type-specific manner. The greater colocalization of myostatin with stem cells provides a mechanism for the impaired myogenic capacity of aged muscle.-

 

[Michael Scally MD]

The Frailty Syndrome

Frailty has only recently been defined as a clinical syndrome with criteria for diagnosis. Prior to the mid 1990’s, the term frail was used to describe older persons who were disabled, failed to thrive, were institutionalized or near the end of life. There was no consensus as to what defined “frailty”. In the mid to late 1990’s, researchers proposed that frailty be defined as a state in which there was a dependence on others for performing functions of daily living. Later this group developed a Frailty Index, a longer Clinical Frailty Scale and a brief screening tool known as “FRAIL”, which was amended to include the following criteria: fatigue, disease, weight loss, inability to walk a short distance and inability to climb a flight of stairs. At about the same time, others proposed that frailty be “diagnosed” if two or more impairments were noted in any one of four areas: physical functioning, nutritional adequacy, cognition and sensory ability.

In early 2000, the phenotype of frailty was described that put forth objective diagnostic measures for in an effort to separate the concept of frailty from disability and co-morbidity. The criteria established for frailty included: the loss of 10 pounds or more in a year, self-reported exhaustion, and weakness - as measured by a progressive decrease in grip strength, reductions in gait speed and declines in physical activity. Frailty was distinguished from frank disability, in that it was a 1) predecessor to disability, 2) there was an event or stressor that catapulted the frail older adult into frank disability and 3) the syndrome was a complex interaction between several factors, including but not limited to: natural physiological alterations seen in aging, co-morbid disease inception and/or progression, nutriture and nutritional inadequacy, cumulative negative environmental impact, genetics, and lifestyle choices. Recent investigations have focused on the cumulative role of inflammatory processes on the development and progression of frailty in the older adult. Pro-inflammatory cytokines, dysregulation of the immunological redundancy pathways, and activation of promoter genes having catabolic effects are thought to be pivotal in the frailty syndrome.

Frailty is often correlated with the presence of pathological conditions in the older adult. These include: anemia, orthostasis, weight loss, sarcopenia, anorexia, polypharmacy, congestive heart failure, diabetes mellitus, osteopenia, hypovitaminosis D, testosterone deficiency, low protein intake, deficits in protein trafficking, declines in cognitive functioning, inflammation with increased cytokine production and decreased regulatory peptides, among others. While weight loss and sarcopenia are central to the clinical manifestations of frailty, the older obese population is equally at risk. Obese persons are generally not thought of as frail, which results in low rates of screening and detection. Obesity in the absence of physical activity leads to sarcopenia and increases in fat mass, which in turn, leads to conditions correlated with frailty and its progression to frank disability. The frail obese or “sarcopenic obese” are a rapidly growing segment of the older adult population and the condition is associated with the greatest health care burdens. Central obesity is of particular concern, with its associations to metabolic syndrome and rapid deterioration in physical functioning. In 2007, the European, Canadian and American Geriatric Advisory Panel failed to reach consensus on a universal “definition” of frailty or on a single “tool” to be used in assessing the syndrome. Several working “clinical definitions” and “tools” were considered useful and appropriate for frailty in the obese and non-obese older adult.

Frailty in the older adult, and the easy progression to disability with the addition of another stressor, results in a domino effect that increases mortality. Prevention is far more cost effective than treatment and should be the first line of defense. Screening and early intervention are key. Due to the difficulties in getting accurate measurements that screen for and/or index the degree of frailty, such as with self-reports of fatigue, several tools and rating scales have been developed over the past decade. Education of practitioners regarding the frailty syndrome, screening and indexing, prevention, intervention and progression, is essential to curtail the rapid increases in disability and health care expenditures expected with the burgeoning aging population. The clinical definitions, epidemiology, mechanisms, interactions, assessment, prevention, and treatments pertaining to frailty in older adults will be addressed in this review.


Heuberger RA. The frailty syndrome: a comprehensive review. J Nutr Gerontol Geriatr 2012;30(4):315-68. Taylor & Francis Online :: The Frailty Syndrome: A Comprehensive Review - Journal of Nutrition in Gerontology and Geriatrics - Volume 30, Issue 4

The frailty syndrome is defined as unintentional weight and muscle loss, exhaustion, and declines in grip strength, gait speed, and activity. Evidence with respect to the clinical definition, epidemiology, mechanisms, interactions, assessment, prevention, and treatment of frailty in the older adult is reviewed.

 

[Michael Scally MD]

Russ D, Gregg-Cornell K, Conaway M, Clark B. Evolving concepts on the age-related changes in “muscle quality”. Journal of Cachexia, Sarcopenia and Muscle 2012:1-15. http://www.springerlink.com/content/u400w8658h7711j7/fulltext.pdf

The deterioration of skeletal muscle with advancing age has long been anecdotally recognized and has been of scientific interest for more than 150 years. Over the past several decades, the scientific and medical communities have recognized that skeletal muscle dysfunction (e.g., muscle weakness, poor muscle coordination, etc.) is a debilitating and life-threatening condition in the elderly. For example, the age-associated loss of muscle strength is highly associated with both mortality and physical disability. It is well-accepted that voluntary muscle force production is not solely dependent upon muscle size, but rather results from a combination of neurologic and skeletal muscle factors, and that biologic properties of both of these systems are altered with aging. Accordingly, numerous scientists and clinicians have used the term “muscle quality” to describe the relationship between voluntary muscle strength and muscle size. In this review article, we discuss the age-associated changes in the neuromuscular system—starting at the level of the brain and proceeding down to the subcellular level of individual muscle fibers—that are potentially influential in the etiology of dynapenia (age-related loss of muscle strength and power).

 

[Michael Scally MD]

Sakuma K, Yamaguchi A. Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass. J Cachexia Sarcopenia Muscle. http://www.springerlink.com/content/7k7234715q7k6766/fulltext.pdf

Recent advances in our understanding of the biology of muscle, and how anabolic and catabolic stimuli interact to control muscle mass and function, have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle occurs as a consequence of several chronic diseases (cachexia) as well as normal aging (sarcopenia). Although many negative regulators [Atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-kappaB), myostatin, etc.] have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of mediators markedly differs among these conditions. Sarcopenic and cachectic muscles have been demonstrated to be abundant in myostatin- and apoptosis-linked molecules. The ubiquitin-proteasome system (UPS) is activated during many different types of cachexia (cancer cachexia, cardiac heart failure, chronic obstructive pulmonary disease), but not many mediators of the UPS change during sarcopenia. NF-kappaB signaling is activated in cachectic, but not in sarcopenic, muscle. Some studies have indicated a change of autophagic signaling during both sarcopenia and cachexia, but the adaptation remains to be elucidated. This review provides an overview of the adaptive changes in negative regulators of muscle mass in both sarcopenia and cachexia.

 

[BBC3]

FIRST - Spelling is noted on my previous omission "apoptosis" LOL...

Second this is a great thread...! Good articles doc... !

Sakuma K, Yamaguchi A. Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass. J Cachexia Sarcopenia Muscle. http://www.springerlink.com/content/7k7234715q7k6766/fulltext.pdf

Recent advances in our understanding of the biology of muscle, and how anabolic and catabolic stimuli interact to control muscle mass and function, have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle occurs as a consequence of several chronic diseases (cachexia) as well as normal aging (sarcopenia). Although many negative regulators [Atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-kappaB), myostatin, etc.] have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of mediators markedly differs among these conditions. Sarcopenic and cachectic muscles have been demonstrated to be abundant in myostatin- and apoptosis-linked molecules. The ubiquitin-proteasome system (UPS) is activated during many different types of cachexia (cancer cachexia, cardiac heart failure, chronic obstructive pulmonary disease), but not many mediators of the UPS change during sarcopenia. NF-kappaB signaling is activated in cachectic, but not in sarcopenic, muscle. Some studies have indicated a change of autophagic signaling during both sarcopenia and cachexia, but the adaptation remains to be elucidated. This review provides an overview of the adaptive changes in negative regulators of muscle mass in both sarcopenia and cachexia.

 

[Michael Scally MD]

Lee S-J, Huynh TV, Lee Y-S, et al. Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin/activin signaling pathway. Proceedings of the National Academy of Sciences. Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin/activin signaling pathway

Myostatin and activin A are structurally related secreted proteins that act to limit skeletal muscle growth. The cellular targets for myostatin and activin A in muscle and the role of satellite cells in mediating muscle hypertrophy induced by inhibition of this signaling pathway have not been fully elucidated. Here we show that myostatin/activin A inhibition can cause muscle hypertrophy in mice lacking either syndecan4 or Pax7, both of which are important for satellite cell function and development. Moreover, we show that muscle hypertrophy after pharmacological blockade of this pathway occurs without significant satellite cell proliferation and fusion to myofibers and without an increase in the number of myonuclei per myofiber. Finally, we show that genetic ablation of Acvr2b, which encodes a high-affinity receptor for myostatin and activin A specifically in myofibers is sufficient to induce muscle hypertrophy. All of these findings are consistent with satellite cells playing little or no role in myostatin/activin A signaling in vivo and render support that inhibition of this signaling pathway can be an effective therapeutic approach for increasing muscle growth even in disease settings characterized by satellite cell dysfunction.

 

[Michael Scally MD]

Mitchell WK, Williams J, Atherton P, Larvin M, Lund J, Narici M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol 2012;3:260. Frontiers | Sarcopenia, Dynapenia, and the Impact of Advancing Age on Human Skeletal Muscle Size and Strength; a Quantitative Review | Frontiers in Striated Muscle Physiology

Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. This demands recognition of the concept of muscle quality; that is the force generating per capacity per unit cross-sectional area (CSA). An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the etiology of sarcopenia. Cross-sectional studies comparing young (18-45 years) and old (>65 years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75 years, muscle mass is lost at a rate of 0.64-0.70% per year in women and 0.80-00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75 years, strength is lost at a rate of 3-4% per year in men and 2.5-3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2-5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass.

 

[Michael Scally MD]

Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013;493(7432):338-45. mTOR is a key modulator of ageing and age-related disease

Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.

 

[Michael Scally MD]

White TA, Lebrasseur NK. Myostatin and Sarcopenia: Opportunities and Challenges - A Mini-Review. Gerontology. Gerontology - Myostatin and Sarcopenia: Opportunities and Challenges - A Mini-Review - FullText - Karger Publishers

The progressive loss of skeletal muscle mass, strength and/or function with advancing age, termed sarcopenia, poses a major threat to independence and quality of life. Therefore, there is significant merit in better understanding the biology of sarcopenia and developing therapeutic interventions to prevent, slow or reverse its progression. Since the discovery of myostatin, a potent negative regulator of growth that is highly enriched in skeletal muscle, there has been great interest in it as a potential mediator of sarcopenia as well as a therapeutic target. The complex biology of myostatin, the promise of myostatin inhibition as an effective means to counter sarcopenia, and the challenges facing its clinical translation are reviewed herein.

 

[Michael Scally MD]

O'Connell MD, Wu FC. Androgen effects on skeletal muscle: implications for the development and management of frailty. Asian J Androl. Androgen effects on skeletal muscle: implications for the development and management of frailty O'Connell MD, Wu FC, - Asian J Androl

Androgens have potent anabolic effects on skeletal muscle and decline with age in parallel to losses in muscle mass and strength. This loss of muscle mass and function, known as sarcopenia, is the central event in development of frailty, the vulnerable health status that presages adverse outcomes and rapid functional decline in older adults. The potential role of falling androgen levels in the development of frailty and their utility as function promoting therapies in older men has therefore attracted considerable attention. This review summarizes current concepts and definitions in muscle ageing, sarcopenia and frailty, and evaluates recent developments in the study of androgens and frailty. Current evidence from observational and interventional studies strongly supports an effect of androgens on muscle mass in ageing men, but effects on muscle strength and particularly physical function have been less clear. Androgen treatment has been generally well-tolerated in studies of older men, but concerns remain over higher dose treatments and use in populations with high cardiovascular risk. The first trials of selective androgen receptor modulators (SARMs) suggest similar effects on muscle mass and function to traditional androgen therapies in older adults. Important future directions include the use of these agents in combination with exercise training to promote functional ability across different populations of older adults, as well as more focus on the relationships between concurrent changes in hormone levels, body composition and physical function in observational studies.

 

[Michael Scally MD]

Elabd C, Cousin W, Upadhyayula P, et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun 2014;5. http://www.nature.com/ncomms/2014/140610/ncomms5082/full/ncomms5082.html

The regenerative capacity of skeletal muscle declines with age. Previous studies suggest that this process can be reversed by exposure to young circulation; however, systemic age-specific factors responsible for this phenomenon are largely unknown.

Here we report that oxytocin—a hormone best known for its role in lactation, parturition and social behaviours—is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age.

Inhibition of oxytocin signalling in young animals reduces muscle regeneration, whereas systemic administration of oxytocin rapidly improves muscle regeneration by enhancing aged muscle stem cell activation/proliferation through activation of the MAPK/ERK signalling pathway. We further show that the genetic lack of oxytocin does not cause a developmental defect in muscle but instead leads to premature sarcopenia.

Considering that oxytocin is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent skeletal muscle ageing.