Skeletal Muscle Decline Research Articles

Features of trunk muscle wasting during acute care and physical function recovery with aortic disease.

BackgroundLow skeletal muscle area or density, such as myosteatosis, identified on computed tomography (CT) is associated with poor prognosis in patients with cardiovascular diseases. However, there is a lack of evidence regarding the clinical process of skeletal muscle decline as a short‐term change during acute care settings. This study focused on the use of routine CT imaging for aortic disease management and investigated the changes in skeletal muscle before and after acute care.MethodsThis prospective study included 123 patients who underwent abdominal CT before and after acute care. The all‐abdominal and each abdominal muscle areas were divided into eight parts (e.g. rectus abdominis, psoas, and erector spine), and their areas and densities were measured at the third lumbar vertebra level after the patients were discharged and de‐identified with blinding to avoid measurement bias. Short physical performance battery (SPPB) was measured at the start and end of in‐hospital cardiac rehabilitation. A generalized linear model with patients as random effects was made to investigate skeletal muscle loss during acute care. Multivariate linear regression analysis was also used to assess the relationship between the change in skeletal muscle during acute care and SPPB during in‐hospital cardiac rehabilitation.ResultsThe median age of the patients was 70 (interquartile: 58–77) years, and 69.9% (86/123) were men. The median day between acute care from the day of surgery or hospital admission and follow‐up CT was 7 (interquartile: 3–8) days. Overall muscle density declined after acute care (estimate value: −3.640, 95% confidence interval [CI]: −4.538 to −2.741), and each abdominal muscle density consistently declined (interaction: F value = 0.099, P = 0.998). In contrast, there was no significant change in the overall muscle area (estimate value: −0.863, 95% CI: −2.925 to 1.200). Changes in the muscle area were different for each skeletal muscle (interaction: F value = 2.142, P = 0.037), and only the erector spine muscle significantly declined (estimate value: −1.836, 95% CI: −2.507 to −1.165). After adjusting for confounding factors, a greater decline in muscle density was associated with lower recovery score on SPPB (β = 0.296, 95% CI: 0.066 to 0.400).ConclusionsMuscle density consistently declined after acute care, especially the erector spine muscles, which also significantly decreased in size. A higher decline in muscle density was associated with a slower recovery of physical function during in‐hospital cardiac rehabilitation in patients with aortic diseases.

RNA-sequencing Reveals a Gene Expression Signature in Skeletal Muscle of a Mouse Model of Age-associated Postoperative Functional Decline.

This study aimed to characterize the effects of laparotomy on postoperative physical function and skeletal muscle gene expression in male C57BL/6N mice at 3, 20, and 24 months of age to investigate late-life vulnerability and resiliency to acute surgical stress. Pre and postoperative physical functioning was assessed by forelimb grip strength on postoperative day (POD) 1 and 3 and motor coordination on POD 2 and 4. Laparotomy-induced an age-associated postoperative decline in forelimb grip strength that was the greatest in the oldest mice. While motor coordination declined with increasing age at baseline, it was unaffected by laparotomy. Baseline physical function as stratified by motor coordination performance (low functioning vs high functioning) in 24-month-old mice did not differentially affect postlaparotomy reduction in grip strength. RNA sequencing of soleus muscles showed that laparotomy-induced age-associated differential gene expression and canonical pathway activation with the greatest effects in the youngest mice. Examples of such age-associated, metabolically important pathways that were only activated in the youngest mice after laparotomy included oxidative phosphorylation and NRF2-mediated oxidative stress response. Analysis of lipid mediators in serum and gastrocnemius muscle showed alterations in profiles during aging and confirmed an association between such changes and functional status in gastrocnemius muscle. These findings demonstrate a mouse model of laparotomy which recapitulated some features of postoperative skeletal muscle decline in older adults, and identified age-associated, laparotomy-induced molecular signatures in skeletal muscles. Future research can build upon this model to study molecular mechanisms of late-life vulnerability and resiliency to acute surgical stress.

Decline of ergothioneine in frailty and cognition impairment.

Ergothioneine is a well-known antioxidant that is abundant in both human red blood cells and in fission yeast responding to nutritional stress. In frail elderly people, whose ageing organs undergo functional decline, there is a correlation between ergothioneine levels and cognitive, but not skeletal muscle decline. In patients suffering from dementia, including Alzheimer's disease with hippocampal atrophy, deteriorating cognitive ability is correlated with declining ergothioneine levels. S-methyl-ergothioneine, trimethyl-histidine and three other trimethyl-ammonium compounds also decrease sharply in dementia, whereas compounds such as indoxyl-sulfate and quinolinic acid increase, possibly exacerbating the disease. Using these opposing dementia markers, not only diagnosis, but also therapeutic interventions to mitigate cognitive decline may now become possible.

Body Composition and Incident Heart Failure in Older Adults: Results From 2 Prospective Cohorts.

BackgroundAging is associated with central fat redistribution and skeletal muscle decline, yet the relationships of tissue compartments with heart failure (HF) remain incompletely characterized. We assessed the contribution of body composition to incident HF in elders.Methods and ResultsParticipants from 2 older cohorts who completed dual‐energy X‐ray absorptiometry (DEXA) and, in one cohort, computed tomography were included. We evaluated associations with incident HF for DEXA principal components (PCs) and total lean, appendicular lean, total fat and trunk fat mass; and for computed tomography measures of abdominal visceral and subcutaneous fat, thigh muscle, intermuscular fat area and thigh muscle density. DEXA analysis included 3621, and computed tomography analysis 2332 participants. During median follow‐up of 11.8 years, 927 participants developed HF. DEXA principal components showed no relationship with HF. After adjustment for height, weight, and cardiovascular risk factors, total lean mass was near significantly associated with higher HF (hazard ratio [HR], 1.25 per SD [1.00–1.56]), whereas total fat mass and thigh muscle density were significantly related to lower HF (HR, 0.82 [0.68–0.99] and HR, 0.87 [0.78–0.97], respectively). Patterns were similar for HF subtypes. The relationships with HF for total lean and fat mass were attenuated after adjusting for intercurrent atrial fibrillation or excluding high natriuretic peptide levels.ConclusionsTotal lean mass was positively associated, while total fat mass and thigh muscle density were inversely associated, with incident HF. These findings highlight the limitations of DEXA for assessment of HF risk in elders and support the preeminence of computed tomography–measured skeletal muscle quality over mass as a determinant of HF incidence.

Abstract 11116: Relationship Between Skeletal Muscle Decline During Acute Care and Recovery of Physical Function in Patients with Aortic Disease

Introduction: Low skeletal muscle area or density identified on computed tomography (CT) is associated with poor prognosis in patients with cardiovascular disease. However, there is a lack of evidence regarding the clinical process of skeletal muscle decline as a longitudinal change in the acute care setting. Hypothesis: Skeletal muscle loss occurs after acute care, and a high degree of skeletal muscle loss is associated with an insufficient recovery of physical function. Methods: This study used routinely acquired CT images for aortic disease management and prospectively reviewed the data of 123 patients who underwent abdominal CT before and after acute care. The area and density of all abdominal muscles and each muscle (such as the rectus abdominis, psoas, and erector spinae) divided into eight parts were measured at the third lumbar vertebra level after patient blinding. The short physical performance battery (SPPB) was used as a physical function parameter at the start and end of in-hospital cardiac rehabilitation. A generalized linear model with patients as random effects was used to investigate skeletal muscle loss during acute care. Multivariate linear regression analysis was performed to assess the relationship between skeletal muscle decline during acute care and the change in SPPB results during inpatient cardiac rehabilitation. Results: The median patient age was 70 years, and 70% of patients were men. All and each abdominal muscle density declined consistently after acute care (interaction: P = 0.998). In contrast, the whole muscle area was found to have no significant change, and the changes were different for each skeletal muscle (interaction: P = 0.037). After adjusting for confounding factors, greater declines in muscle density were associated with lower recovery on the SPPB (β = 0.30, P = 0.007). Conclusions: Muscle density declines consistently after acute care, and a greater decline in muscle density is associated with a lower recovery of physical function during in-hospital cardiac rehabilitation in patients with aortic disease.

Abstract 14355: Metabolic Dysregulation and Incident Atrial Fibrillation in Older Adults

Introduction: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and post-load levels of glucose and non-esterified fatty acids (NEFA) reflect different facets of metabolic regulation, but their contributions to AF risk have not been studied simultaneously in prior studies. We assessed fasting and post-load glucose and NEFA in an older cohort to identify their independent associations with new-onset AF, and secondarily with baseline ECG parameters known to be markers of AF risk. Methods: This study focused on participants from the community-based Cardiovascular Health Study who were free of prevalent AF and had serum collected in the fasting state and after an oral glucose tolerance test. Maximal p wave duration and p wave terminal force in V1 (PTFV1) were measured from 12-lead ECG. Associations were evaluated with linear regression for ECG parameters, and Cox regression for AF. Results: The study included 1,877 participants (age 77.7±4.4). After adjustment, both fasting and post-load glucose, but not NEFA, were positively associated with higher PTFV1. When fasting and post-load glucose were entered together, only the relationship for the latter remained significant (63 μV*ms greater PTFV1 per SD increment in post-load glucose [p=0.028]). During median follow-up of 11.4 years, 717 cases of incident AF occurred. Post-load glucose, but not fasting glucose or either NEFA measure, showed an association with incident AF (adj. HR per SD=1.11 [95% CI=1.02, 1.21], p=0.017). There was significant interaction by sex (p=0.015). The positive relationship of post-load glucose with AF was observed in women (adj. HR per SD=1.21 [1.09, 1.35], p<0.001), but not men (adj. HR per SD=0.97 [0.85, 1.12], p=0.714). Conclusions: Among older adults, post-load glucose, but not fasting glucose or NEFA measures, was positively associated with incident AF, with consistent findings for PTFV1 on baseline ECG. The relationship with AF appeared specific to women. Because post-load glucose is a marker of both pancreatic β-cell insufficiency and skeletal muscle decline, these findings suggest that interventions to address such tissue-organ dysfunction in older women might prevent AF in this high-risk population.

Abstract 12796: Fasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and Its Subtypes in Older Adults

Introduction: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and postprandial levels are under different homeostatic regulation. The relationships of fasting and postload glucose and NEFA with incident HF and its subtypes remain incompletely defined. Methods: We hypothesized that fasting and postload glucose and NEFA are positively associated with incident HF in older adults, with postload levels bearing stronger associations. Serum glucose and NEFA levels were measured during fasting and 2 hours post oral glucose tolerance test in the Cardiovascular Health Study. HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) were examined secondarily. Results: Among 2238 people (age 78±4) with median follow-up of 9.9 years, there were 737 HF events (257 classifiable as HFpEF, 197 as HFrEF). After adjustment for demographic and lifestyle factors (main model), both fasting (HR per SD 1.11 [95% CI 1.01-1.23]) and postload (HR per SD 1.14 [1.05-1.24]) glucose was significantly associated with incident HF. No association was seen for fasting or postload NEFA. When adjusted for each other, only postload glucose (HR 1.11 [1.003-1.22]), but not fasting glucose (HR 1.06 [0.94-1.20]), remained associated with HF. Further adjustment for prevalent atherosclerotic cardiovascular disease, atrial fibrillation and other risk factors in the causal pathway did not affect the association for postload glucose, but eliminated that for fasting glucose. There was no interaction by sex, but associations for fasting and postload glucose appeared stronger with higher BMI (p<0.025). Assessment of HF subtypes showed no associations for glucose or NEFA with HFpEF. Both fasting glucose (HR 1.23 [1.03-1.48]) and postload glucose (HR 1.24 [1.07-1.45]) were significantly associated with HFrEF, but relationships disappeared on mutual adjustment. Conclusions: Fasting and postload glucose, but not NEFA, were associated with incident HF, particularly HFrEF. The association proved especially robust for postload glucose, which reflects pancreatic β-cell insufficiency and skeletal muscle decline. Our findings suggest that targeting relevant pathways in these two organ-tissues could offer new approaches for HF prevention in elders.

Exercise attenuates juvenile irradiation-induced skeletal muscle decline by improving calcium handling and decreasing mitochondrial stress

Proper skeletal muscle development, maintenance, and function is necessary for movement. Decline in muscle function with age and disease is directly associated with a diminished quality of life. Radiation therapy is commonly used to treat certain forms of childhood cancer based on the cytotoxic effects of radiation on cancerous tissue. However, the adverse effects elicited by radiation are not always constrained to the diseased tissue and can accelerate muscle wasting and decline, which is particularly detrimental to juvenile cancer survivors. Exercise is effective at limiting muscle decline and improving muscle function in various diseases. Thus, we hypothesized 1 mo of voluntary endurance exercise following juvenile radiation treatment will reduce muscle damage and restore functional deficits that occur following radiation. Here, we show that following juvenile radiation, 1 mo of voluntary wheel running significantly improved muscle function in mice by promoting adaptations in intracellular calcium handling, improving mitochondrial turnover and reducing oxidative stress resulting from radiation-induced mitochondrial damage. These findings help guide caregivers in their approach to childhood cancer survivor recovery and have implications for other diseases where similar mechanisms of calcium handling and mitochondrial function are disrupted.

Should Estimated Glomerular Filtration Rate Be Adjusted for Race?

Should Estimated Glomerular Filtration Rate Be Adjusted for Race?

Age-Related Changes in the Matrisome of the Mouse Skeletal Muscle.

Aging is characterized by a progressive decline of skeletal muscle (SM) mass and strength which may lead to sarcopenia in older persons. To date, a limited number of studies have been performed in the old SM looking at the whole, complex network of the extracellular matrix (i.e., matrisome) and its aging-associated changes. In this study, skeletal muscle proteins were isolated from whole gastrocnemius muscles of adult (12 mo.) and old (24 mo.) mice using three sequential extractions, each one analyzed by liquid chromatography with tandem mass spectrometry. Muscle sections were investigated using fluorescence- and transmission electron microscopy. This study provided the first characterization of the matrisome in the old SM demonstrating several statistically significantly increased matrisome proteins in the old vs. adult SM. Several proteomic findings were confirmed and expanded by morphological data. The current findings shed new light on the mutually cooperative interplay between cells and the extracellular environment in the aging SM. These data open the door for a better understanding of the mechanisms modulating myocellular behavior in aging (e.g., by altering mechano-sensing stimuli as well as signaling pathways) and their contribution to age-dependent muscle dysfunction.

Chronic intermittent hypoxia aggravates skeletal muscle aging by down-regulating Klc1/grx1 expression via Wnt/β-catenin pathway

ObjectiveSleep breathing disorder may affect skeletal muscle decline in the elderly, but the mechanism is not clear. Therefore, this study explores the mechanism of skeletal muscle aging in chronic intermittent hypoxia (CIH) rats. MethodsIn vitro and in vivo CIH models were constructed in L6 cells and SD rats by treating chronic intermittent hypoxia. Pathological changes of skeletal muscle in vivo were measured by hematoxylin-eosin (HE) staining. Cell proliferation and apoptosis were detected by CCK-8 and Flow cytometer, respectively. The expression of KLC1/GRX1 and the proteins related to the Wnt/β-catenin pathway were measured by qRT-PCR and western blot. ResultsCIH model was successfully established induced by chronic intermittent hypoxia with lower skeletal muscle index (SMI), increased inward migration of muscle fiber cell nucleus, and muscle cells’ distance. The results showed that Wnt/β-catenin signalling was activatedin both L6 cells and CIH rats’ model. KLC1 and GRX1 were significantly downregulated in the CIH model. Loss of function showed that downregulation of KLC1 promoted L6 cell and skeletal muscle aging in vitro and in vivo, respectively. ConclusionOur results demonstrated that CIH aggravated skeletal muscle aging by down-regulating KLC1/GRX1 expression via the Wnt/β-catenin pathway.

GRSF1 deficiency in skeletal muscle reduces endurance in aged mice.

GRSF1 is a mitochondrial RNA-binding protein important for maintaining mitochondrial function. We found that GRSF1 is highly expressed in cultured skeletal myoblasts differentiating into myotubes. To understand the physiological function of GRSF1 in vivo, we generated mice in which GRSF1 was specifically ablated in skeletal muscle. The conditional knockout mice (Grsf1cKO) appeared normal until 7-9 months of age. Importantly, however, a reduction of muscle endurance compared to wild-type controls was observed in 16- to 18-month old Grsf1cKO mice. Transcriptomic analysis revealed more than 200 mRNAs differentially expressed in Grsf1cKO muscle at this age. Notably, mRNAs encoding proteins involved in mitochondrial function, inflammation, and ion transport, including Mgarp, Cxcl10, Nfkb2, and Sln mRNAs, were significantly elevated in aged Grsf1cKO muscle. Our findings suggest that GRSF1 deficiency exacerbates the functional decline of aged skeletal muscle, likely through multiple downstream effector proteins.

Plantar mechanical stimulation attenuates protein synthesis decline in disused skeletal muscle via modulation of nitric oxide level

Both research conducted under microgravity conditions and ground-based space analog studies have shown that air pump-based plantar mechanical stimulation (PMS) of cutaneous mechanoreceptors of the sole of the foot is able to increase neuromuscular activity in the musculature of the lower limbs. This type of stimulation is able to attenuate unloading-induced skeletal muscle atrophy and impaired muscle function. The aim of the present study was to evaluate the effects of PMS on anabolic signaling pathways in rat soleus muscle following 7-day hindlimb suspension (HS) and to elucidate if the effects of PMS on anabolic processes would be NO-dependent. The soles of the feet were stimulated with a frequency of 1-s inflation/1-s deflation with a total of 20 min followed by 10 min rest. This cycle was repeated for 4 h each day. We observed a decrease in the soleus muscle mass after 7-day HS, which was not prevented by PMS. We also observed a decrease in slow-type fiber cross-sectional area (CSA) by 56%, which significantly exceeded a decrease (–22%) in fast-type fiber CSA. PMS prevented a reduction in slow-twitch fiber CSA, but had no effect on fast-twitch fiber CSA. PMS prevented a 63% decrease in protein synthesis after 7-day HS as well as changes in several key anabolic signaling regulators, such as p70S6k, 4E-BP1, GSK3β, eEF-2, p90RSK. PMS also prevented a decrease in the markers of translational capacity (18S and 28S rRNA, c-myc, 45S pre-rRNA). Some effects of PMS on anabolic signaling were altered due to NO-synthase inhibitor (L-NAME) administration. Thus, PMS is able to partially prevent atrophic processes in rat soleus muscle during 7-day HS, affecting slow-type muscle fibers. This effect is mediated by alterations in anabolic signaling pathways and may depend on NO-synthase activity.

Model‐based analysis of microcirculatory parameters affecting O 2 transport in skeletal muscle subjected to fixed surface PO 2

Microcirculation in skeletal muscle determines both blood flow distribution and O2 transport. The partial pressure of oxygen (PO2) is a prime candidate to assess in tissue, as PO2 variations herald a functionality decline in skeletal muscle. Traditional non-invasive microcirculatory techniques such as Intra-vital Video Microscopy (IVVM) allowing for blood velocity and capillary saturation (SO2) measurements, are unable to directly assess skeletal muscle tissue PO2. Instead, modern microcirculatory O2 analysis relies on biophysical models to recreate tissue PO2 distributions. (Ellis et al, Microcirc 2012, 19:5). Recently, a continuous coupled partial differential equation (PDE) model of two layers of skeletal muscle coupled via diffusion at their boundaries was developed accounting for tissue O2 diffusion, capillary O2 convection, tissue O2 consumption, and capillary-tissue O2 transfer. This model was developed to study an IVVM protocol involving a controlled exposure of skeletal muscle using an O2 exchange chamber. In the protocol studied, hemodynamic parameters in the skeletal muscle region near to the O2 chamber are experimentally shown to exhibit substantial variations. The prevailing theory is capillary perfusion limits the depth of penetration of the chamber O2, and local hemodynamic parameter responses serve to regulate capillary SO2 in skeletal muscle; this would be towards either a fixed target value or homogeneity with neighboring capillary modules. The coupled PDE two-layer model was developed for steady-state PO2 distributions and was solved using traditional math techniques such as operator decoupling and Fourier decomposition, and exhibited the ability to rapidly and accurately calculate PO2 distributions in skeletal muscle which agreed with experimental values. (Afas and Goldman, Vasc Bio 2020). The solution affords for the unique ability not allowed in previous convection-diffusion analytic models of O2 transport, to observe the interaction of both skeletal muscle layers. This is achieved by assuming baseline hemodynamic parameters in the layer far from the O2 chamber and allowing the near layer to take on a range of parameter variations; these variations can be compared to experimental observations. In this study, the behavior of both layers of skeletal muscle adjacent to an O2 chamber will be modelled by the a-priori fixing of parameters in the region far from the O2 chamber and allowing near-layer parameters to be perturbed. Several parameters, including capillary density φ, velocity vB, inlet saturation SIN, hematocrit HT, and tissue consumption μ will have this variation method applied from previous baselines (Afas et al, Math Biosci 2021, in press), and the resultant two-layer O2 profiles will be visualized, as well as the conditions under which the capillary SO2 is homogenized in both layers of skeletal muscle.

Short-Term Immobilization Promotes a Rapid Loss of Motor Evoked Potentials and Strength That Is Not Rescued by rTMS Treatment.

Short-term limb immobilization results in skeletal muscle decline, but the underlying mechanisms are incompletely understood. This study aimed to determine the neurophysiologic basis of immobilization-induced skeletal muscle decline, and whether repetitive Transcranial Magnetic Stimulation (rTMS) could prevent any decline. Twenty-four healthy young males (20 ± 0.5 years) underwent unilateral limb immobilization for 72 h. Subjects were randomized between daily rTMS (n = 12) using six 20 Hz pulse trains of 1.5 s duration with a 60 s inter-train-interval delivered at 90% resting Motor Threshold (rMT), or Sham rTMS (n = 12) throughout immobilization. Maximal grip strength, EMG activity, arm volume, and composition were determined at 0 and 72 h. Motor Evoked Potentials (MEPs) were determined daily throughout immobilization to index motor excitability. Immobilization induced a significant reduction in motor excitability across time (−30% at 72 h; p < 0.05). The rTMS intervention increased motor excitability at 0 h (+13%, p < 0.05). Despite daily rTMS treatment, there was still a significant reduction in motor excitability (−33% at 72 h, p < 0.05), loss in EMG activity (−23.5% at 72 h; p < 0.05), and a loss of maximal grip strength (−22%, p < 0.001) after immobilization. Interestingly, the increase in biceps (Sham vs. rTMS) (+0.8 vs. +0.1 mm, p < 0.01) and posterior forearm (+0.3 vs. +0.0 mm, p < 0.05) skinfold thickness with immobilization in Sham treatment was not observed following rTMS treatment. Reduced MEPs drive the loss of strength with immobilization. Repetitive Transcranial Magnetic Stimulation cannot prevent this loss of strength but further investigation and optimization of neuroplasticity protocols may have therapeutic benefit.

Melatonin role in skeletal muscle disorders.

This review discusses the impact of the neuro-hormone melatonin on skeletal muscle disorders based on recent literature data with the aim to clarify the utility of the melatonin therapy in patients affected by muscle diseases. It has been pointed out the possible role of melatonin as a food supplement to cure muscular disorders characterized by muscle wasting. Oxidative damage has been proposed as one of the major contributors of the skeletal muscle decline occurring both in physiological and pathological conditions. It is known that excessive oxidant levels lead to mitochondrial damage, and in turn, contribute to apoptotic signaling activation and autophagic impairment. This condition is common in a variety of skeletal muscle disorders. The scientific evidence enhances the antioxidant effect of melatonin, that has been demonstrated by several studies both in vitro and in vivo. This effect counteracts mitochondrial impairments and reduces oxidative stress and autophagic alterations in muscle fibers. Its beneficial role in restoring muscle decline, takes place mainly in atrophic conditions correlated to muscle aging. The findings of the research suggest that melatonin may be considered as a valid dietary supplement, useful to prevent muscle wasting, in particular, in sarcopenia-associated diseases.

SARCOPENIA IN PRIMARY CARE: SCREENING, DIAGNOSIS, MANAGEMENT.

Detection of sarcopenia in primary care is a first and essential step in community-dwelling older adults before implementing preventive interventions against the onset of disabling conditions. In fact, leaving this condition undiagnosed and untreated can impact on the individual's quality of life and function, as well as on healthcare costs. This article summarizes the many instruments today available for promoting an earlier and prompter detection of sarcopenia in primary care, combining insights about its clinical management. Primary care physicians may indeed play a crucial role in the identification of individuals exposed to the risk of sarcopenia or already presenting this condition. To confirm the suspected diagnosis, several possible techniques may be advocated, but it is important that strategies are specifically calibrated to the needs, priorities and resources of the setting where the evaluation is conducted. To tackle sarcopenia, nutritional counselling and physical activity programs are today the two main interventions to be proposed. Multicomponent and personalized exercise programs can (and should) be prescribed by primary care physicians, taking advantage of validated programs ad hoc designed for this purpose (e.g., the Vivifrail protocol). It is possible that, in the next future, new pharmacological treatments may become available for tackling the skeletal muscle decline. These will probably find application in those individuals non-responding to lifestyle interventions.

Chemoradiation impairs myofiber hypertrophic growth in a pediatric tumor model

Pediatric cancer treatment often involves chemotherapy and radiation, where off-target effects can include skeletal muscle decline. The effect of such treatments on juvenile skeletal muscle growth has yet to be investigated. We employed a small animal irradiator to administer fractionated hindlimb irradiation to juvenile mice bearing implanted rhabdomyosarcoma (RMS) tumors. Hindlimb-targeted irradiation (3 × 8.2 Gy) of 4-week-old mice successfully eliminated RMS tumors implanted one week prior. After establishment of this preclinical model, a cohort of tumor-bearing mice were injected with the chemotherapeutic drug, vincristine, alone or in combination with fractionated irradiation (5 × 4.8 Gy). Single myofiber analysis of fast-contracting extensor digitorum longus (EDL) and slow-contracting soleus (SOL) muscles was conducted 3 weeks post-treatment. Although a reduction in myofiber size was apparent, EDL and SOL myonuclear number were differentially affected by juvenile irradiation and/or vincristine treatment. In contrast, a decrease in myonuclear domain (myofiber volume/myonucleus) was observed regardless of muscle or treatment. Thus, inhibition of myofiber hypertrophic growth is a consistent feature of pediatric cancer treatment.

Flavonoids from dark chocolate and (−)-epicatechin ameliorate high-fat diet-induced decreases in mobility and muscle damage in aging mice

Age-related muscle decline, when associated with obesity, leads to adverse outcomes with increased risks for falling, loss of independence, disability and risk of premature mortality. The aim of this study was to assess the potential beneficial effects of flavonoids in improving the age-/high-fat-diet-induced decrease in physical activity/capacity related to the onset of skeletal muscle decline. The effects of the administration of a cocoa beverage enriched with flavanols or pure (−)-epicatechin for 5 wk in a model of physical activity decline induced by the ingestion of a high-fat diet (60% fat) in middle-age mice were evaluated. The results showed that both products, the cocoa beverage enriched with flavanols and pure (−)-epicatechin, improved physical performance evaluated with the hang-wire, inverted-screen, and weight-lifting tests and dynamometry compared with the performance of the controls. The beverage and (−)-epicatechin increased the follistatin/myostatin ratio and increased the expression of myocyte enhancer factor 2A (MEF2A), suggesting an effect on molecular modulators of growth differentiation. Furthermore, the beverage and (−)-epicatechin decreased the expression of O-type fork-head transcription factor (FOXO1A) and muscle ring finger 1 (MURF1) markers of the skeletal muscle ubiquitin-proteasome degradation pathway.

Skeletal Muscle Gene Expression in Long-Term Endurance and Resistance Trained Elderly.

Physical exercise is deemed the most efficient way of counteracting the age-related decline of skeletal muscle. Here we report a transcriptional study by next-generation sequencing of vastus lateralis biopsies from elderly with a life-long high-level training practice (n = 9) and from age-matched sedentary subjects (n = 5). Unsupervised mixture distribution analysis was able to correctly categorize trained and untrained subjects, whereas it failed to discriminate between individuals who underwent a prevalent endurance (n = 5) or a prevalent resistance (n = 4) training, thus showing that the training mode was not relevant for sarcopenia prevention. KEGG analysis of transcripts showed that physical exercise affected a high number of metabolic and signaling pathways, in particular those related to energy handling and mitochondrial biogenesis, where AMPK and AKT-mTOR signaling pathways are both active and balance each other, concurring to the establishment of an insulin-sensitive phenotype and to the maintenance of a functional muscle mass. Other pathways affected by exercise training increased the efficiency of the proteostatic mechanisms, consolidated the cytoskeletal organization, lowered the inflammation level, and contrasted cellular senescence. This study on extraordinary individuals who trained at high level for at least thirty years suggests that aging processes and exercise training travel the same paths in the opposite direction.