Decline In Skeletal Muscle Mass Research Articles

Experimental Models of Sarcopenia: Bridging Molecular Mechanism and Therapeutic Strategy.

Sarcopenia has been defined as a progressive decline of skeletal muscle mass, strength, and functions in elderly people. It is accompanied by physical frailty, functional disability, falls, hospitalization, and mortality, and is becoming a major geriatric disorder owing to the increasing life expectancy and growing older population worldwide. Experimental models are critical to understand the pathophysiology of sarcopenia and develop therapeutic strategies. Although its etiologies remain to be further elucidated, several mechanisms of sarcopenia have been identified, including cellular senescence, proteostasis imbalance, oxidative stress, and “inflammaging.” In this article, we address three main aspects. First, we describe the fundamental aging mechanisms. Next, we discuss both in vitro and in vivo experimental models based on molecular mechanisms that have the potential to elucidate the biochemical processes integral to sarcopenia. The use of appropriate models to reflect sarcopenia and/or its underlying pathways will enable researchers to understand sarcopenia and develop novel therapeutic strategies for sarcopenia. Lastly, we discuss the possible molecular targets and the current status of drug candidates for sarcopenia treatment. In conclusion, the development of experimental models for sarcopenia is essential to discover molecular targets that are valuable as biochemical biomarkers and/or therapeutic targets for sarcopenia.

P1569ADIPONECTIN IS ASSOCIATED WITH DECLINE IS SKELETAL MUSCLE MASS AND BONE MINERAL CONTENT IN PATIENTS ON HEMODIALYSIS

Abstract Background and Aims Patients on hemodialysis are prone to undernutrition, malnutrition-inflammation-atherosclerosis (MIA) syndrome, and protein-energy wasting (PEW). One of the major adipocytokines adiponectin (ADPN) is involved in anti-arteriosclerotic and anti-inflammatory processes. However, ADPN is implicated in muscle weakness and loss of muscle mass in the elderly in addition to sarcopenia. At the 2019 ERA-EDTA Congress, we announced that total plasma ADPN levels in patients on hemodialysis (HD) showed a significant inverse correlation with BMI, body fat in percentage, mass and estimated skeletal muscle mass, and ADPN may be involved in sarcopenia in patients on HD. Herein, we investigated the association of ADPN level with sarcopenia in patients on HD using a method different from the one used in our previous study. We examined the relationship between total plasma ADPN level and the rate of change in estimated skeletal muscle mass, bone mineral content, and body fat mass over 5 years after the plasma ADPN measurement. Furthermore, we analyzed whether an elevated ADPN level was predictive of a subsequent decline in these parameters. Method Total plasma ADPN levels were measured using ELISA (Bio Vendor-Laboratorni Medicina a.s., Czech Republic) in 42 male patients on HD (age: 51.1 ± 9.0 years, dialysis vintage: 144.8 ± 99.2 months, BMI: 21.8 ± 3.2, dry BW: 62.0 ± 10.9 kg, dialysis time: 15.6 ± 3.1 hours/week). The estimates of skeletal muscle mass, bone mineral content, and body fat mass were made using multi-frequency bioelectrical impedance analysis (MFBIA) within the same year when total plasma ADPN level were first measured in 2011 as well as in 2016. We then calculated the rates of change in the estimated skeletal muscle mass, bone mineral content, and body fat mass over the 5 years and correlated these parameters with the total plasma ADPN measurements. Results Conclusion Total plasma ADPN levels inversely correlate with larger rates of decrease in estimated skeletal muscle mass and bone mineral content in patients on HD. This suggests that ADPN may play a role in the decline in skeletal muscle mass and bone mineral content over time in patients on HD.

Manipulating Cellular Energetics to Slow Aging of Tissues and Organs.

Up to now numerous studies in the field of gerontology have been published. Nevertheless, a well-known food restriction remains the most reliable and efficient way of lifespan extension. Physical activity is also a well-documented anti-aging intervention being especially efficient in slowing down the age-associated decline of skeletal muscle mass. In this review we focus on the molecular mechanisms of the effect of physical exercise on muscle tissues. We also discuss the possibilities of pharmacological extension of this effect to the rest of the tissues. During the exercise, the level of ATP decreases triggering activation of AMP-dependent protein kinase (AMPK). This kinase stimulates antioxidant potential of the cells and their mitochondrial respiratory capacity. The exercise also induces mild oxidative stress, which, in turn, mediates the stimulation via hormetic response. Furthermore, during the exercise cells generate activators of mammalian target of rapamycin (mTOR). The intracellular ATP level increases during the rest periods between exercises thus promoting mTOR activation. Therefore, regular exercise intermittently activates anti-oxidant defenses and mitochondrial biogenesis (via AMPK and the hormetic response) of the muscle tissue, as well as its proliferative potential (via mTOR), which, in turn, impedes the age-dependent muscle atrophy. Thus, the intermittent treatment with activators of (i) AMPK combined with the inducers of hormetic response and of (ii) mTOR might partly mimic the effects of physical exercise. Importantly, pharmacological activation of AMPK takes place in the absence of ATP level decrease. The use of uncouplers of respiration and oxidative phosphorylation at the phase of AMPK activation could also prevent negative consequences of the cellular hyper-energization. It is believed that the decline of both antioxidant and proliferative potentials of the cells causes the age-dependent decline of multiple tissues, rather than only the muscular one. We argue that the approach above is applicable for the majority of tissues in an organism.

A cross-sectional study of the relationships between different components of sarcopenia and brachial ankle pulse wave velocity in community-dwelling elderly

BackgroundPrevious studies have just found skeletal muscle mass decline is associated with arterial stiffness, but it is unclear whether muscle strength and physical performance as important compositions of sarcopenia are associated with arterial stiffness. The aim of this study was to investigate the relationship between sarcopenia, the components of sarcopenia and arterial stiffness among elderly in the community.MethodsThis study enrolled 450 elderly people who received general medical examinations in Tianjin First Center Hospital. Each of the subjects was greater than 65 years old, including 266 male and 184 female subjects. Based on the diagnostic criteria for sarcopenia in older people developed by the Asian Working Group for Sarcopenia (AWGS), 89 subjects were separated into the sarcopenia group. The living habits, disease status, general status and laboratory examinations of all subjects were collected. The body composition (including appendicular skeletal muscle mass and visceral fat area (VFA) of each participant) was measured by bioimpedance analysis. HS, usual gait speed (GS), and brachial ankle pulse wave velocity (baPWV) were measured.ResultsSarcopenia subjects had higher baPWV, nutrition risk and lower appendicular skeletal muscle index (ASMI), Handgrip strength (HS), GS, body mass index (BMI), triacylglycerol (TG), serum albumin (ALB) and creatinine (Cr) than did non-sarcopenia subjects; Sarcopenia subjects also had higher visceral fat area (VFA) than did non-sarcopenia subjects (p < 0.05). ASMI and HS were negatively associated with baPWV (t = − 5.807, p = 0.000 and t = − 3.085, p = 0.002), but the relationship between baPWV and GS was not statistically significant (t = − 0.862, p = 0.389) by multivariable linear regression. After adjusting for confounders, a multivariate logistic regression analysis revealed that sarcopenia was related with age, BMI, sports and baPWV in community dwelling elderly.ConclusionsASMI and HS were negatively associated with baPWV in community dwelling elderly in China; and baPWV was a risk factor of sarcopenia.

SUN-256 LOW MUSCLE MASS IN HEMODIALYSIS PATIENT IS ASSOCIATED WITH NON-CORONARY VASCULAR CALCIFICATION AND MAJOR CARDIOVASCULAR OUTCOME

Sarcopenia is characterized by age-related decline of skeletal muscle mass with low muscle strength or functional disabilities. According to recent studies, noncoronary vascular calcification was negatively correlated with sarcopenia. We aimed to investigate correlation between sarcopenia and quantified vascular calcification score (VCS) of the arm including vascular access. And also evaluate the relationships between low muscle mass and incidence of vascular intervention and major cardiac and cerebrovascular events (MACCE). Non-contrast arm CT scan including vascular access was taken. Later, VCS was measured by using Aquarius Ver. 4.4.12 simulating the Agatston Method. Skeletal muscle mass was estimated using multi-frequency bioelectrical impedance (BIA, Inbody S10) in supine position checked after a midweek dialysis session. Low muscle mass (LMM) group was defined as patients whose skeletal muscle mass at both lower extremities measured by BIA, normalized to height-squared was less than the median. Vascular Calcification (VC) was assigned to patients with a cut-off value of 500 or higher, which is 40% of highest VC. Data are presented as median (25th to 75th percentile) for continuous variables or a frequency (percentage) for categorical variables. Statistical differences in the clinical characteristics between the two groups were determined using the Mann-Whitney U test for continuous variables and the chi-square test for categorical variables. Univariate and multivariate logistic regression analyses were used to determine the association between LMM and VC. We enrolled clinically stable 75 adult patients with hemodialysis. In the total 75 patients, there were 42 males (56.0%), and the median age was 64 (58-72) years. All but two patients met the diagnostic criteria for sarcopenia defined by previous study investigated in Koreans. The median vintage of hemodialysis was 49.4 (32.1-99.2) months. When dividing the patients into two groups based on skeletal muscle mass at both legs, there were no differences between the 2 groups in sex, ESRD etiology, and type of vascular access. However, Age and HD vintage were significantly older in LMM group. LMM was significantly associated with VC (Hazard ratio (HR) 3.562, 95% CI 1.341-9.463, p=0.011). After adjusting age, sex, HD vintage, systolic blood pressure and diabetes, LMM was independently associated with VC (HR 10.415, 95% CI 2.357-46.024, p=0.002). Since interventions can occur multiple times in one patient and each intervention is not independent, the Prentice, Williams and Peterson Total Time survival analysis model was used. Vascular intervention was not significantly associated with LMM (HR 1.391, 95% CI 0.746-2.594, p=0.299). In addition, MACCE did not show significant association with LMM (HR 0.989, 95% CI 0.503-1.943, p=0.974). Low muscle mass is associated with vascular calcification in hemodialysis patients. And low muscle mass could be suggested as another potential predictor of vascular calcification.

The Role of Nutrition in Attenuating Age-Related Skeletal Muscle Atrophy.

The elderly population is increasing rapidly worldwide, and we are faced with the significant challenge for maintaining or improving physical activity, independence, and quality of life. Sarcopenia, the age-related decline of skeletal muscle mass, is characterized by loss of muscle quantity and quality resulting to a gradual slowing of movement, a decrease in strength and power, elevated risk of fall-related injury, and often frailty. Supplemental, hormonal, and pharmacological approaches have been attempted to attenuate sarcopenia but these have not achieved outstanding results. In this review, we summarize the current knowledge of nutrition-based therapies for counteracting sarcopenia.

Diaphragm muscle sarcopenia into very old age in mice.

Sarcopenia is the age‐related decline of skeletal muscle mass and function. Diaphragm muscle (DIAm) sarcopenia may contribute to respiratory complications, a common cause of morbidity and mortality in the elderly. From 6 to 24 months (mo) of age, representing ~100% and ~80% survival in C57BL/6 × 129 male and female mice, there is a significant reduction in DIAm force generation (~30%) and cross‐sectional area (CSA) of type IIx and/or IIb muscle fibers (~30%), impacting the ability to perform high force, non‐ventilatory behaviors. To date, there is little information available regarding DIAm sarcopenia in very old age groups. The present study examined DIAm sarcopenia in C57BL/6 × 129 male and female mice at 24, 27, and 30 mo, representing ~80%, ~60%, and ~30% survival, respectively. We hypothesized that survival into older ages will show no further worsening of DIAm sarcopenia and functional impairment in 30 mo mice compared to 24 or 27 mo C57BL/6 × 129 mice. Measurements included resting ventilation, transdiaphragmatic pressure (Pdi) generation across a range of motor behaviors, muscle fiber CSA, and proportion of type‐identified DIAm fibers. Maximum Pdi and resting ventilation did not change into very old age (from 24 to 30 mo). Type IIx and/or IIb fiber CSA and proportions did not change into very old age. The results of the study support a critical threshold for the reduction in DIAm force and Pdi such that survival into very old age is not associated with evidence of progression of DIAm sarcopenia or impairment in ventilation.

Genetic Associations with Aging Muscle: A Systematic Review.

The age-related decline in skeletal muscle mass, strength and function known as ‘sarcopenia’ is associated with multiple adverse health outcomes, including cardiovascular disease, stroke, functional disability and mortality. While skeletal muscle properties are known to be highly heritable, evidence regarding the specific genes underpinning this heritability is currently inconclusive. This review aimed to identify genetic variants known to be associated with muscle phenotypes relevant to sarcopenia. PubMed, Embase and Web of Science were systematically searched (from January 2004 to March 2019) using pre-defined search terms such as “aging”, “sarcopenia”, “skeletal muscle”, “muscle strength” and “genetic association”. Candidate gene association studies and genome wide association studies that examined the genetic association with muscle phenotypes in non-institutionalised adults aged ≥50 years were included. Fifty-four studies were included in the final analysis. Twenty-six genes and 88 DNA polymorphisms were analysed across the 54 studies. The ACTN3, ACE and VDR genes were the most frequently studied, although the IGF1/IGFBP3, TNFα, APOE, CNTF/R and UCP2/3 genes were also shown to be significantly associated with muscle phenotypes in two or more studies. Ten DNA polymorphisms (rs154410, rs2228570, rs1800169, rs3093059, rs1800629, rs1815739, rs1799752, rs7412, rs429358 and 192 bp allele) were significantly associated with muscle phenotypes in two or more studies. Through the identification of key gene variants, this review furthers the elucidation of genetic associations with muscle phenotypes associated with sarcopenia.

AGS and NIA Bench-to Bedside Conference Summary: Osteoporosis and Soft Tissue (Muscle and Fat) Disorders.

This report summarizes the presentations and recommendations of the eleventh annual American Geriatrics Society and National Institute on Aging research conference, "Osteoporosis and Soft Tissue (Muscle/Fat) Disorders," on March 11-12, 2019, in Bethesda, Maryland. Falls, fractures, and sarcopenia have a major impact on health in older adults, and they are interconnected by known risk factors. The link between osteoporosis, which is common in older adults, and the risk of falls is well known. Sarcopenia, the age-related decline in skeletal muscle mass and function, is also associated with an increased risk of falls and fractures because it reduces strength and leads to functional limitations. In addition to increasing the risk of falls, sarcopenia and osteoporosis can lead to frailty, reduced quality of life, morbidity, and mortality. The conference highlighted the impact of bone and soft tissue disorders on quality of life, morbidity, and mortality in older adults. Presenters described factors that contribute to these disorders; health disparities experienced by various subpopulations; and promising biological, pharmacologic, and behavioral interventions to prevent or treat these disorders. The workshop identified many research gaps and questions along with research recommendations that have the potential to enhance the prospect of healthy aging and improved quality of life for older adults. J Am Geriatr Soc 68:31-38, 2019.

HAND2 TRANSCRIPTION FACTOR ENHANCES NMJ ORGANIZATION AND FUNCTION IN OLD MICE

Over time, declining muscle force and power leads to mobility disability and impaired quality of life. In aging rodents and humans, a denervation and reinnervation process is strongly implicated in sarcopenia: the progressive decline of skeletal muscle mass, composition, and function. We propose that the concomitant decline in expression of Hand2, a key transcription factor (TF) for sympathetic neuron maintenance, induces motor pre- and postsynaptic neuromuscular junction (NMJ) instability and disorganization. To counter the deleterious effect of sympathetic denervation, we developed a novel viral vector (AAV9-Hand2-eGFP, Hand2) carrying Hand2 expression exclusively to sympathetic neurons. Male and female, 16-month-old mice, were examined for signs of muscle denervation and sarcopenia 6 months after IV injection with either Hand2 or control empty virus (AAV9-eGFP, EV). We found that Hand2 increased preterminal synaptic vesicle release, neurofilament phosphorylation (Neurite length: Hand2: 3732±496 µm, EV: 2674±165 µm; P <0.01), NMJ pre/postterminal co-localization, hindlimb muscle mass (EDL: 25%, soleus: 14%, tibialis anterior: 17% and gastrocnemius: 25%; n = 6-8 muscles per treatment group; P < 0.01), myofiber cross-sectional area, and protein kinase-A RIIα/RIα ratio (EV, RIIα:1.05±0.03, RIα:0.93±0.04, ratio: 1.13; Hand2, RIIα:1.81±0.03, RIα:0.94±0.03, ratio: 1.94; P<0.001) which contributes to stability of the NMJ. We also examined Hand2 gene methylation, and RNA-sequencing, muscle metabolomics, and whole body and muscle function with aging in EV and Hand2 injected mice. Our data indicate that expression of Hand2 significantly enhances skeletal muscle adrenergic receptor signaling through the canonical pathway, and prevents in NMJ transmission, and muscle mass and function decline with aging.

Protein intake per day and at each daily meal and skeletal muscle mass declines among older community dwellers in Japan.

To examine associations between protein intake per day and at different meals and skeletal muscle mass declines. Two-year prospective cohort study among older community dwellers. National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) in Japan. Older men (n 292) and women (n 363) aged 60-87 years who participated in the baseline (2006-2008) and follow-up studies (2008-2010) of NILS-LSA and did not exhibit low skeletal muscle mass at baseline. Muscle mass was assessed using dual-energy X-ray absorptiometry at baseline and follow-up. Low muscle mass was defined as skeletal muscle mass index <7·0 kg/m2 for men and <5·4 kg/m2 for women at follow-up. Daily protein intake and protein intake at each meal were calculated from 3 d dietary records at baseline and sex-stratified tertiles were determined. Mean (sd) protein intake at breakfast, lunch and dinner was 22·7 (7·8), 26·7 (9·3) and 37·4 (10·5) g for men and 19·3 (6·3), 23·2 (7·3) and 28·5 (7·0) g for women, respectively. After adjusting for age, baseline skeletal muscle mass and other confounders in logistic modelling, greater total protein intake was associated with lower prevalence of skeletal muscle mass decline among men at follow-up (P = 0·024). Particularly, the OR (95 % CI) for high lunchtime protein intake was low (0·11 (0·02, 0·61); P = 0·01). No significant association between total protein intake and prevalence of skeletal muscle mass decline was found among women. High total protein intake, particularly at lunchtime, is associated with retention of skeletal muscle mass in men.

Milk and resistance exercise intervention to improve muscle function in community-dwelling older adults at risk of sarcopenia (MIlkMAN): protocol for a pilot study

IntroductionSarcopenia is a progressive muscle disorder characterised by decline in skeletal muscle mass, strength and function leading to adverse health outcomes, including falls, frailty, poor quality of life and death....

Sarcopenia in Ovarian Cancer Patients, Oncologic Outcomes Revealing the Importance of Clinical Nutrition: Review of Literature.

Ovarian cancer is the leading cause of death among gynecological malignancies. Its usual clinical manifestation is at advanced stages, with nutritional impairment, weight loss, and a consequent decline in skeletal muscle mass and strength (defined as sarcopenia). The relationship between sarcopenia and decreased survival was demonstrated not only in ovarian cancer but also in other cancer types, such as hepatocellular, pancreatic, lung, colon, cervical, metastatic breast, and renal cancer. The aim of this study is to review the current evidence regarding the relationship between sarcopenia and the surgical and oncological outcomes in ovarian cancer patients. The systematic search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRSIMA) statement. The terms "SARCOPENIA" AND "OVARIAN CANCER" were systematically used to search PubMed and Scopus databases. Original reports in English language were identified, with the purpose to include all relevant papers regarding the role of sarcopenia and indicators of skeletal muscle quality assessment in gynecological ovarian cancer. A total of 9 studies were considered eligible for the present review. The strength of recommendation was moderate and the level of evidence was low in all selected articles. No prospective studies were conducted and most of the papers were case-control series comparing ovarian cancer sarcopenic population vs. non sarcopenic population. Sarcopenia appears to have an important role in oncological outcomes of ovarian cancer patients. However, sarcopenia occurrence during disease history and mechanisms underlying the possible impairment in prognosis should be better investigated. Prospective trials are awaited in order to obtain a better insight in this topic.

LOW SKELETAL MUSCLE MASS IS ASSOCIATED WITH INCREASED ARTERIAL STIFFNESS IN COMMUNITY-DWELLING ELDERLY INDIVIDUALS

Objective: Age-related decline of skeletal muscle mass, known as sarcopenia, is related to insulin resistance, inflammation, and oxidative stress. The aim of this study was to investigate the association between low skeletal muscle mass and arterial stiffness in a community-dwelling elderly individuals. Design and method: Study participants consisted of general population who participated in the Wakayama Health Promotion Study (the Wakayama Study). Of the participants, 1795 apparently healthy elderly individuals (mean age; 71 ± 5 years) without a history of treatment for cardiovascular disease, renal disease and orthopedic disease were enrolled in this study. Bioelectrical impedance analysis was performed to estimate appendicular skeletal muscle mass (ASM). A value of ASM was normalized for height and conversed to an ASM index. The brachial-ankle pulse wave velocity (baPWV) was measured using a simple automatic oscillometric technique with an appropriate size cuff. Results: The ASM and ASM index were 11.1 ± 2.5 kg and 4.4 ± 0.7 kg/m2 respectively, and were significantly lower in females than in males (p < 0.001). The subjects were divided into subgroups according to sex-specific percentiles of ASM index and were defined as sarcopenic group (<15 percentile) and normal group (>=15 percentile). In females and males, the baPWV was significantly higher in sarcopenic group than normal group after adjusting for potential confounders (females: 17.7 ± 4.1m/s vs. 17.2 ± 3.3m/s, P = 0.001; males: 18.6 ± 4.0m/s vs. 17.4 ± 3.5m/s, P < 0.001). Multiple regression analysis revealed that ASM index was associated with baPWV independent of age, obesity, systolic BP, antihypertensive medication and diabetes mellitus (females: β = −0.147, P < 0.001; males: β = −0.192, P < 0.001). Conclusions: In elderly individuals, the excessive loss of skeletal muscle mass is significantly associated with increase of arterial stiffness, and may lead to greater risk of cardiovascular events.

447-P: Low Muscle Mass Is Associated with Carotid Atherosclerosis in Korean Men with Type 2 Diabetes

Background: Sarcopenia, an age-related decline in skeletal muscle mass, leads to metabolic and vascular abnormalities. However, little is known regarding the independent relationship between skeletal muscle mass and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to evaluate the association of skeletal muscle mass with markers of carotid atherosclerosis, carotid intima-media thickness (CIMT) and carotid artery plaque, in men and women with T2DM. Methods: In this cross-sectional study, a total of 8,918 patients (4,520 men and 4,398 women) with T2DM were recruited from the outpatient clinic of Huh’s Diabetes Center from 2003 to 2016. Skeletal muscle mass was estimated from bioimpedance analysis measurements and skeletal muscle mass index (SMI, %) was defined as skeletal muscle mass (kg)/total body weight (kg) × 100. Carotid ultrasonography was performed to measure mean CIMT of both common carotid arteries. Carotid artery plaque was defined as a focal structure protruding into the lumen of the vessel of ≥50% than the surrounding area. Results: In both men and women, the presence of carotid artery plaque was higher with decreasing SMI quartiles. In men, this association remained significant after adjustment for additional risk factors (ptrend &amp;lt;0.001). Odds ratio for having carotid artery plaque was 1.76 (95% confidence interval [CI] 1.34-2.33; p &amp;lt;0.001) in men with lowest SMI quartile compared with highest quartile. However, in women, the association was attenuated after adjustment for additional risk factors. There was no significant association between SMI quartiles and CIMT in both men and women. Conclusion: Low muscle mass is associated with the presence of carotid artery plaque in men with T2DM. Disclosure M. Nam: None. D. Seo: None. M. Jung: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None. Funding National Research Foundation of Korea (2017R1D-1A1B03034581)

RNA-binding proteins: The next step in translating skeletal muscle adaptations?

The decline of skeletal muscle mass during illness, injury, disuse, and aging is associated with poor health outcomes. Therefore, it is important to pursue a greater understanding of the mechanisms that dictate skeletal muscle adaptation. In this review, we propose that RNA-binding proteins (RBPs) comprise a critical regulatory node in the orchestration of adaptive responses in skeletal muscle. While RBPs have broadly pleiotropic molecular functions, our discussion is constrained at the outset by observations from hibernating animals, which suggest that RBP regulation of RNA stability and its impact on translational reprogramming is a key component of skeletal muscle response to anabolic and catabolic stimuli. We discuss the limited data available on the expression and functions of RBPs in adult skeletal muscle in response to disuse, aging, and exercise. A model is proposed in which dynamic changes in RBPs play a central role in muscle adaptive processes through their differential effects on mRNA stability. While limited, the currently available data suggest that understanding how adaptive (and maladaptive) changes in the expression of RBPs regulate mRNA stability in skeletal muscle could be an informative and productive research area for finding new strategies to limit atrophy and promote hypertrophy.

Effects of IGF-1 isoforms on muscle growth and sarcopenia.

The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin‐like growth factor‐1 (IGF‐1) has been implicated in many anabolic pathways in skeletal muscle. IGF‐1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF‐1Ea and IGF‐1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF‐1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF‐1Ea or IGF‐1Eb transgenes was protective against age‐related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1‐α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF‐1Ea and MLC/IGF‐1Eb mice during aging. These data suggest that IGF‐1 is a promising therapeutic agent in staving off advancing muscle weakness.

Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis.

Diabetes mellitus is associated with various disorders of the locomotor system including the decline in mass and function of skeletal muscle. The mechanism underlying this association has remained ambiguous, however. We now show that the abundance of the transcription factor KLF15 as well as the expression of genes related to muscle atrophy are increased in skeletal muscle of diabetic model mice, and that mice with muscle-specific KLF15 deficiency are protected from the diabetes-induced decline of skeletal muscle mass. Hyperglycemia was found to upregulate the KLF15 protein in skeletal muscle of diabetic animals, which is achieved via downregulation of the E3 ubiquitin ligase WWP1 and consequent suppression of the ubiquitin-dependent degradation of KLF15. Our results revealed that hyperglycemia, a central disorder in diabetes, promotes muscle atrophy via a WWP1/KLF15 pathway. This pathway may serve as a therapeutic target for decline in skeletal muscle mass accompanied by diabetes mellitus.

Dose-Dependent Increases in Whole-Body Net Protein Balance and Dietary Protein-Derived Amino Acid Incorporation into Myofibrillar Protein During Recovery from Resistance Exercise in Older Men

ABSTRACTBackgroundAge-related decline in skeletal muscle mass is at least partly attributed to anabolic resistance to food intake. Resistance exercise sensitizes skeletal muscle tissue to the anabolic properties of amino acids.ObjectiveThe present study assessed protein digestion and amino acid absorption kinetics, whole-body protein balance, and the myofibrillar protein synthetic response to ingestion of different amounts of protein during recovery from resistance exercise in older men.MethodsForty-eight healthy older men [mean ± SEM age: 66 ± 1 y; body mass index (kg/m2): 25.4 ± 0.3] were randomly assigned to ingest 0, 15, 30, or 45 g milk protein concentrate after a single bout of resistance exercise consisting of 4 sets of 10 repetitions of leg press and leg extension and 2 sets of 10 repetitions of lateral pulldown and chest press performed at 75–80% 1-repetition maximum. Postprandial protein digestion and amino acid absorption kinetics, whole-body protein metabolism, and myofibrillar protein synthesis rates were assessed using primed, continuous infusions of l-[ring-2H5]-phenylalanine, l-[ring-2H2]-tyrosine, and l-[1-13C]-leucine combined with ingestion of intrinsically l-[1-13C]-phenylalanine and l-[1-13C]-leucine labeled protein.ResultsWhole-body net protein balance showed a dose-dependent increase after ingestion of 0, 15, 30, or 45 g of protein (0.015 ± 0.002, 0.108 ± 0.004, 0.162 ± 0.008, and 0.215 ± 0.009 μmol Phe · kg−1 · min−1, respectively; P < 0.001). Myofibrillar protein synthesis rates were higher after ingesting 30 (0.0951% ± 0.0062%/h, P = 0.07) or 45 g of protein (0.0970% ± 0.0062%/h, P < 0.05) than after 0 g (0.0746% ± 0.0051%/h). Incorporation of dietary protein–derived amino acids (l-[1-13C]-phenylalanine) into de novo myofibrillar protein showed a dose-dependent increase after ingestion of 15, 30, or 45 g protein (0.0171 ± 0.0017, 0.0296 ± 0.0030, and 0.0397 ± 0.0026 mole percentage excess, respectively; P < 0.05).ConclusionsDietary protein ingested during recovery from resistance exercise is rapidly digested and absorbed. Whole-body net protein balance and dietary protein-derived amino acid incorporation into myofibrillar protein show dose-dependent increases. Ingestion of ≥30 g protein increases postexercise myofibrillar protein synthesis rates in older men. This trial was registered at Nederlands Trial Register as NTR4492.

Prospective Views for Whey Protein and/or Resistance Training Against Age-related Sarcopenia.

Skeletal muscle aging is characterized by decline in skeletal muscle mass and function along with growing age, which consequently leads to age-related sarcopenia, if without any preventive timely treatment. Moreover, age-related sarcopenia in elder people would contribute to falls and fractures, disability, poor quality of life, increased use of hospital services and even mortality. Whey protein (WP) and/or resistance training (RT) has shown promise in preventing and treating age-related sarcopenia. It seems that sex hormones could be potential contributors for gender differences in skeletal muscle and age-related sarcopenia. In addition, skeletal muscle and the development of sarcopenia are influenced by gut microbiota, which in turn is affected by WP or RT. Gut microbiota may be a key factor for WP and/or RT against age-related sarcopenia. Therefore, focusing on sex hormones and gut microbiota may do great help for preventing, treating and better understanding age-related sarcopenia.