Sarcopenia, the age-related loss of skeletal muscle mass, is a significant public health concern that continues to grow in relevance as the population ages. Certain conditions have the strong potential to coincide with sarcopenia to accelerate the progression of muscle atrophy in older adults. Among these conditions are co-morbid diseases common to older individuals such as cancer, kidney disease, diabetes, and peripheral artery disease. Furthermore, behaviors such as poor nutrition and physical inactivity are well-known to contribute to sarcopenia development. However, we argue that these behaviors are not inherent to the development of sarcopenia but rather accelerate its progression. In the present review, we discuss how these factors affect systemic and cellular mechanisms that contribute to skeletal muscle atrophy. In addition, we describe gaps in the literature concerning the role of these factors in accelerating sarcopenia progression. Elucidating biochemical pathways related to accelerated muscle atrophy may allow for improved discovery of therapeutic treatments related to sarcopenia.
Aging; Proteolysis; Satellite Cells; HIV; COPD; Disability
Age-related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high- and low-functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low-functioning elderly (LFE) participants when compared to young and high-functioning elderly (HFE) participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in COX activity. Levels of key metabolic regulators, SIRT3 and PGC-1α were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects, however no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery (PIM) components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways, and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.
aging; sarcopenia; mitochondria; skeletal muscle; PGC-1α
Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) up-regulation of pro-inflammatory mediators (e.g., TNF-α, IL-1β, 6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-κB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity.
molecular inflammation; aging; calorie restriction; exercise; cytokines; oxidative stress; inflammatory diseases; age-related diseases; obesity; sarcopenia; dementia; atherosclerosis; cancer; osteoporosis
Study reports clinical and functional outcomes of surgical treatment in a case series of nine patients with distal fibular tumours.
Nine patients with distal fibular tumours were observed between 2005 and 2010. A PubMed search was performed using the terms “fibula”, “lower limb tumour [cancer]”, “sarcoma”, “Ewing”, “peroneal”, “fibular metastasis”, and “limb-salvage surgery”.
In all our patients, lesions were unilateral. All patients complained of pain; limping was present in 5 of 9 tumours. Patients were managed surgically, except one who underwent local radiotherapy. In six patients, a benign or tumor-like lesion was detected. Malignancies consisted of metastatic lung adenocarcinoma (two cases) or multifocal mesenchymal cancer (one case). Non-malignant lesions were treated by curettage and filling, followed by internal fixation when needed. In malignant or locally aggressive lesions, metadiaphyseal fibular resection was performed. The literature search retrieved either case reports or small case series, reflecting the rarity of distal fibular tumours. Surgical treatment was successful in all patients with benign lesions, whereas the rate of success was 40–100 % in case of malignancies.
Given the low incidence of distal fibular tumours, controversies exist about the optimal surgical management. Clinical observation and imaging should be reserved to asymptomatic benign lesions. In non-malignant tumours causing pain, limping, and pathological fractures; in malignancies, surgery is recommended. Finally, in patients with asymptomatic lesions of uncertain nature, biopsy and histological examination should be performed to plan appropriate management.
The prevalence of cardiovascular disease (CVD) increases with advancing age. While the long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of CVD, intrinsic cardiac aging enhances the susceptibility to developing heart pathologies in late life. The progressive decline of cardiomyocyte mitochondrial function is considered to be a major mechanism underlying heart senescence. Damaged mitochondria not only produce less ATP, but also generate increased amounts of reactive oxygen species (ROS) and display a greater propensity to trigger apoptosis. Given the post-mitotic nature of cardiomyocytes, the efficient removal of dysfunctional mitochondria is critical for the maintenance of cell homeostasis, as damaged organelles cannot be diluted by cell proliferation. The only known mechanism whereby mitochondria are turned over is through macroautophagy (MA). The efficiency of this process declines with advancing age which may play a critical role in heart senescence as well as in age-related CVD. This review illustrates the putative mechanisms whereby alterations in the autophagic removal of damaged mitochondria intervene in the process of cardiac aging as well as in the pathogenesis of specific heart diseases especially prevalent in late life (e.g., left ventricular hypertrophy, ischemic heart disease, heart failure, and diabetic cardiomyopathy). Interventions proposed to counter cardiac aging through improvements in MA (e.g., calorie restriction and calorie restriction mimetics) are also presented.
heart senescence; mitophagy; oxidative stress; resveratrol; calorie restriction
Deep venous thrombosis (DVT) or pulmonary embolism (PE) is a rare, but not exceptional presentation of soft tissue sarcomas (STSs). Due to the remarkable difference in the incidence between DVT or PE and STSs, this type of STS presentation is usually associated with a considerable delay in tumor diagnosis and treatment.
We describe two cases of STS who presented with DVT and PE. Physical and radiographic examination only showed the presence of DVT. Both patients were treated for DVT or PE for several months. Due to the persistence of symptoms and the inefficacy of anticoagulant therapy, magnetic resonance imaging (MRI) was performed, which revealed the presence of a lower limb mass in both cases. The definite diagnosis was reached via excisional biopsy and histological examination.
In one case, MRI showed a large tumor in the anterior muscle compartment of the right thigh, with thrombosis of the right common femoral vein and involvement of the ipsilateral common iliac vein and inferior vena cava until the confluence of the renal veins. In the other case, MRI showed a large tumor in the middle third of the right thigh. The lesion was in close proximity to the superficial femoral vein that appeared compressed and showed signs of thrombosis. In both cases, histological examination revealed a high-grade leiomyosarcoma.
STSs of the lower extremities can rarely present with DVT or PE. This possibility should be considered in the differential diagnosis of painful leg swelling, especially in patients with recurrent or refractory venous thrombosis. When a STS is suspected, MRI should be obtained followed by excisional biopsy of the eventual mass. A delay in diagnosis and treatment of STSs often results in very poor prognosis.
Level of evidence. IV
Leiomyosarcoma; Venous thromboembolism; Lower extremity sarcoma; Pulmonary embolism
The lower extremities are important to performing physical activities of daily life. This study investigated lower extremity tissue composition, i.e. muscle and fat volumes, in young and older adults and the relative importance of individual tissue compartments to the physical function of older adults. A total of 43 older (age 78.3 ± 5.6 yr) and 20 younger (age 23.8 ± 3.9 yr) healthy men and women participated in the study. Older participants were further classified as either high- (HF) or low-functioning (LF) according to the Short Physical Performance Battery (SPPB). Magnetic resonance images were used to determine the volumes of skeletal muscle, subcutaneous fat (SAT), and intermuscular fat (IMAT) in the thigh (femoral) and calf (tibiofibular) regions. After adjusting for the sex of participants, younger participants had more femoral muscle mass than older adults (p < 0.001 for between group differences) as well as less femoral IMAT (p = 0.008) and tibiofibular IMAT (p < 0.001). Femoral muscle was the only tissue compartment demonstrating a significant difference between the two older groups, with HF participants having 31% more femoral muscle mass than LF participants (mean difference = 103.0 ± 34.0 cm3; p = 0.011). In subsequent multiple regression models including tissue compartments and demographic confounders, femoral muscle was the primary compartment associated with both SPPB score (r2 = 0.264, p= 0.001) and 4-meter gait speed (r2 = 0.187, p= 0.007). These data suggest that aging affects all lower extremity compartments, but femoral muscle mass is the major compartment associated with physical function in older adults.
Aging; Sarcopenia; Older Adults; Disability; SPPB; IMAT
Caloric restriction and physical exercise have proven beneficial against age-associated changes in body composition and declining physical performance; however, little is known regarding what benefit these interventions might have when initiated late in life. The study of mimetics of diet and exercise and the combination thereof may provide additional treatments for a vulnerable elderly population; however, how and when to initiate such interventions requires consideration in developing the most safe and efficacious treatment strategies. In this review, we focus on preclinical late-life intervention studies, which assess the relationship between physical function, sarcopenia, and body composition. We provide a conceptual framework for the ever-changing definition of sarcopenia and a rationale for the use of an appropriate rodent model of this condition. We finish by providing our perspective regarding the implications of this body of work and future areas of research that may also contribute to the ultimate goal of extending healthspan.
Renin angiotensin system; Enalapril repamycin; Physical function; Body composition
The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.
Age-related adiposity; Body composition; Sarcopenia; Renin–angiotensin system; Physical function; Muscle quality
Obese older adults are particularly susceptible to sarcopenia and have a higher prevalence of disability than their peers of normal weight. Interventions to improve body composition in late life are crucial to maintaining independence. The main mechanisms underlying sarcopenia have not been determined conclusively, but chronic inflammation, apoptosis, and impaired mitochondrial function are believed to play important roles. It has yet to be determined whether impaired cellular quality control mechanisms contribute to this process. The objective of this study was to assess the effects of a 6-month weight loss program combined with moderate-intensity exercise on the cellular quality control mechanisms autophagy and ubiquitin-proteasome, as well as on inflammation, apoptosis, and mitochondrial function, in the skeletal muscle of older obese women. The intervention resulted in significant weight loss (8.0 ± 3.9 % vs. 0.4 ± 3.1% of baseline weight, p = 0.002) and improvements in walking speed (reduced time to walk 400 meters, − 20.4 ± 16% vs. − 2.5 ± 12%, p = 0.03). In the intervention group, we observed a three-fold increase in messenger RNA (mRNA) levels of the autophagy regulators LC3B, Atg7, and lysosome-associated membrane protein-2 (LAMP-2) compared to controls. Changes in mRNA levels of FoxO3A and its targets MuRF1, MAFBx, and BNIP3 were on average seven-fold higher in the intervention group compared to controls, but these differences were not statistically significant. Tumor necrosis factor-α (TNF-α) mRNA levels were elevated after the intervention, but we did not detect significant changes in the downstream apoptosis markers caspase 8 and 3. Mitochondrial biogenesis markers (PGC1α and TFAm) were increased by the intervention, but this was not accompanied by significant changes in mitochondrial complex content and activity. In conclusion, although exploratory in nature, this study is among the first to report the stimulation of cellular quality control mechanisms elicited by a weight loss and exercise program in older obese women.
β-thalassemia major (βTM) or Cooley anemia is characterized by significantly reduced or absent synthesis of β-globin chains, which induces important pathologic consequences including hemolytic anemia, altered erythropoiesis, and bone marrow overstimulation. The pathogenesis of bone changes in patients with βTM is not yet completely understood. However, an unbalance in bone mineral turnover resulting from increased resorption and suppression of osteoblast activity has been detected in βTM patients. The abnormal regulation of bone metabolism may be related to hormonal and genetic factors, iron overload and iron chelation therapy, nutritional deficits, and decreased levels of physical activity. Here, we review the most recent findings on the physiopathology of bone abnormalities in βTM. Clinical presentation and radiological features of βTM-related bone changes are also discussed.
Preclinical studies strongly suggest that accelerated apoptosis in skeletal myocytes may be involved in the pathogenesis of sarcopenia. However, evidence in humans is sparse. In the present study, we investigated whether apoptotic signaling in the skeletal muscle was associated with indices of muscle mass and function in older persons.
Community-dwelling older adults were categorized into high-functioning (HF) or low-functioning (LF) groups according to their short physical performance battery (SPPB) summary score. Participants underwent an isokinetic knee extensor strength test and 3-dimensional magnetic resonance imaging of the thigh. Vastus lateralis muscle samples were obtained by percutaneous needle biopsy and assayed for the expression of a set of apoptotic signaling proteins. Age, sex, number of comorbid conditions and medications as well as knee extensor strength were not different between groups. HF participants displayed greater thigh muscle volume compared with LF persons. Multivariate partial least squares (PLS) regressions showed significant correlations between caspase-dependent apoptotic signaling proteins and the muscular percentage of thigh volume (R2 = 0.78; Q2 = 0.61) as well as gait speed (R2 = 0.81; Q2 = 0.56). Significant variables in the PLS model of percent muscle volume were active caspase-8, cleaved caspase-3, cytosolic cytochrome c and mitochondrial Bak. The regression model of gait speed was mainly described by cleaved caspase-3 and mitochondrial Bax and Bak. PLS predictive apoptotic variables did not differ between functional groups. No correlation was determined between apoptotic signaling proteins and muscle strength or quality (strength per unit volume).
Data from this exploratory study show for the first time that apoptotic signaling is correlated with indices of muscle mass and function in a cohort of community-dwelling older persons. Future larger-scale studies are needed to corroborate these preliminary findings and determine if down-regulation of apoptotic signaling in skeletal myocytes will provide improvements in the muscle mass and functional status of older persons.
The Progressive Action Short Brace (PASB) is a custom-made thoraco-lumbar-sacral orthosis (TLSO), devised in 1976 by Dr. Lorenzo Aulisa (Institute of Orthopedics at the Catholic University of the Sacred Heart, Rome, Italy). The PASB was designed to overcome the limits imposed by the trunk anatomy. Indeed, the particular geometry of the brace is able to generate internal forces that modify the elastic reaction of the spine. The PASB is indicated for the conservative treatment of lumbar and thoraco-lumbar scoliosis. The aim of this article is to explain the biomechanic principles of the PASB and the rationale underlying its design. Recently published studies reporting the results of PASB-based treatment of adolescent scoliotic patients are also discussed.
Description and principles
On the coronal plane, the upper margin of the PASB, at the side of the curve concavity, prevents the homolateral bending of the scoliotic curve. The opposite upper margin ends just beneath the apical vertebra. The principle underlying such configuration is that the deflection of the inferior tract of a curved elastic structure, fixed at the bottom end, causes straightening of its upper tract. Therefore, whenever the patient bends towards the convexity of the scoliotic curve, the spine is deflected. On the sagittal plane, the inferior margins of the PASB reach the pelvitrochanteric region, in order to stabilize the brace on the pelvis. The transverse section of the brace above the pelvic grip consists of asymmetrical ellipses. This allows the spine to rotate towards the concave side only, leading to the continuous generation of derotating moments. On the sagittal plane, the brace is contoured so as to reduce the lumbar lordosis. The PASB, by allowing only those movements counteracting the progression of the curve, is able to produce corrective forces that are not dissipated. Therefore, the brace is based on the principle that a constrained spine dynamics can achieve the correction of a curve by inverting the abnormal load distribution during skeletal growth.
Since its introduction in 1976, several studies have been published supporting the validity of the biomechanical principles to which the brace is inspired. In this article, we present the outcome of a case series comprising 110 patients with lumbar and thoraco-lumbar curves treated with PASB brace. Antero-posterior radiographs were used to estimate the curve magnitude (CM) and the torsion of the apical vertebra (TA) at 5 time points: beginning of treatment (t1), one year after the beginning of treatment (t2), intermediate time between t1 and t4 (t3), end of weaning (t4), 2-year minimum follow-up from t4 (t5). The average CM value was 29.3°Cobb at t1 and 13.0°Cobb at t5. TA was 15.8° Perdroille at t1 and 5.0° Perdriolle at t5. These results support the efficacy of the PASB in the management of scoliotic patients with lumbar and thoraco-lumbar curves.
The results obtained in patients treated with the PASB confirm the validity of our original biomechanical approach. The efficacy of the PASB derives not only from its unique biomechanical features but also from the simplicity of its design, construction and management.
labile iron; iron accumulation; iron overload; mitochondrial dysfunction; aging
Sarcopenia, loss of muscle mass and function, is a common feature of aging. Oxidative damage and apoptosis are likely underlying factors. Autophagy, a process for the degradation of cellular constituents, may be a mechanism to combat cell damage and death. We investigated the effect of age on autophagy and apoptosis in plantaris muscle of male Fischer344 rats that were either fed ad libitum, or mild, life-long calorie restricted (CR) alone or combined with life-long voluntary exercise. Upstream autophagy regulatory proteins were either upregulated with age (Beclin-1) or unchanged (Atg7 and 9). LC3 gene and protein expression pattern as well as LAMP-2 gene expression, both downstream regulators of autophagy, however, suggested an age-related decline in autophagic degradation. Atg protein expression and LC3 and LAMP-2 gene expression were improved in CR rats with or without exercise. The age-related increase in oxidative damage and apoptosis were attenuated by the treatments. Both, oxidative damage and apoptosis correlated negatively with autophagy. We conclude that mild CR attenuates the age-related impairment of autophagy in rodent skeletal muscle, which might be one of the mechanisms by which CR attenuates age-related cellular damage and cell death in skeletal muscle in vivo.
Autophagy; plantaris; aging; apoptosis; calorie restriction; exercise; wheel running
Background: the existence of a relationship among inflammation, high-density lipoprotein cholesterol (HDL-C) and physical function has been suggested.
Objective: the aim of the study is to investigate the possible interaction of HDL-C on inflammation and physical function.
Design: cross-sectional study.
Setting: town of Tuscania (Italy).
Subjects: all the 329 community-dwelling older persons aged ≥75 years (mean age 79.8 ± 5.2 years, women 56.2%).
Methods: HDL-C, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and interleukin-6 (IL-6) were measured. Activities of daily living (ADL), instrumental ADL (IADL) and 4-m walking speed were assessed. Linear regression models were performed.
Results: given the multiple significant interactions, models were stratified according to HDL-C concentrations. In participants with normal HDL-C concentrations, only IL-6 showed a significant association with IADL (β = −0.439, SE = 0.176, P = 0.01). In participants with low HDL-C concentrations, all three inflammatory biomarkers were significantly associated with 4-m walking speed and IADL. IL-6 was also significantly associated with ADL (β = −0.755, SE = 0.259, P = 0.006), whereas borderline significances were reported for CRP and ESR.
Conclusions: the association between inflammation and physical function is particularly enhanced in elders with low HDL-C concentrations. Though HDL-C may merely act as a wellbeing index, HDL-C concentrations should be considered in studies evaluating inflammation and physical function.
HDL cholesterol; physical function; inflammation; older persons; elderly
Evidence from animal models and preliminary studies in humans indicate that calorie restriction (CR) delays cardiac aging and can prevent cardiovascular disease. These effects are mediated by a wide spectrum of biochemical and cellular adaptations, including redox homeostasis, mitochondrial function, inflammation, apoptosis and autophagy. Despite the beneficial effects of CR, its large-scale implementation is challenged by applicability issues as well as health concerns. However, preclinical studies indicate that specific compounds, such as resveratrol, may mimic many of the effects of CR, thus potentially obviating the need for drastic food intake reductions. Results from ongoing clinical trials will reveal whether the intriguing alternative of CR mimetics represents a safe and effective strategy to promote cardiovascular health and delay cardiac aging in humans.
Cardiovascular disease; oxidative stress; inflammation; apoptosis; autophagy; calorie restriction mimetics
Introduction and objectives
Physical deformities caused by adolescent idiopathic scoliosis (AIS) coupled with conservative treatment of AIS with orthesis unavoidably impacts on patients' quality of life (QoL). The present study aimed at evaluating the QoL in patients affected by AIS treated with brace. The study also sought to determine the ability of different QoL questionnaires to monitor QoL over the course of treatment.
Materials and methods
Data were collected in 108 consecutive patients (96 females, 16 males) affected by AIS admitted to the outpatient orthopaedic clinic of the Catholic University of the Sacred Heart in Rome (Italy). Patients were subjected to full-time (i.e., 22 hrs per day) conservative treatment with the progressive action short brace (PASB), the Lyon brace or a combination of PASB + Lyon brace. Three instruments were used for QoL determination: the Scoliosis Research Society 22 (SRS-22), Bad Sobernheim Stress Questionnaire (BSSQ) and the Brace Questionnaire (BrQ).
A significant correlation was detected among the 3 scores (p < 0.001). The BrQ possesses a higher capacity to detect changes in QoL in relation to the patient gender, type of brace, curve severity at baseline and at the completion of treatment, and curve type. Overall, boys displayed a higher QoL than girls. In all 3 questionnaires, higher QoL scores were determined in patients treated with the PASB compared with those using the Lyon brace. QoL scores were significantly correlated with the curve severity. Higher QoL scores were obtained by participants with thoraco-lumbar curves as compared with those with other curves.
The 3 questionnaires are effective in capturing changes in QoL in AIS patients subjected to conservative treatment. However, the BrQ possesses a higher discriminatory capacity compared with the other questionnaires tested. PASB-based treatment is associated with better QoL than the Lyon bracing.
Loss of cardiac mitochondrial function with age may cause increased cardiomyocyte death through mitochondria-mediated release of apoptogenic factors. We investigated ventricular subsarcolemmal (SSM) and interfibrillar (IFM) mitochondrial bioenergetics and susceptibility towards Ca2+-induced permeability transition pore (mPTP) opening with aging and lifelong calorie restriction (CR). Cardiac mitochondria were isolated from 8, 18, 29 and 37-month-old male Fischer 344 × Brown Norway rats fed either ad libitum (AL) or 40% calorie restricted diets. With age, H2O2 generation did not increase and oxygen consumption did not significantly decrease in either SSM or IFM. Strikingly, IFM displayed an increased susceptibility towards mPTP opening during senescence. In contrast, Ca2+ retention capacity of SSM was not affected by age, but SSM tolerated much less Ca2+ than IFM. Only modest age-dependent increases in cytosolic caspase activities and cytochrome c levels were observed and were not affected by CR. Levels of putative mPTP-modulating components: cyclophilin-D, the adenine nucleotide translocase (ANT), and the voltage-dependent ion channel (VDAC) were not affected by aging or CR. In summary, the age-related reduction of Ca2+ retention capacity in IFM may explain the increased susceptibility to stress-induced cell death in the aged myocardium.
heart disease; ischemia-reperfusion; senescence; hypertrophy
TNF-α-mediated apoptosis is enhanced in aged rodent muscles, suggesting that this pathway may be involved in sarcopenia. Interleukin-15 (IL-15), a muscle-derived anabolic cytokine, mitigates muscle wasting and apoptosis in cachectic rats. This effect is thought to occur through inhibition of TNF-α-triggered apoptosis. We investigated IL-15 signaling and the TNF-α-mediated pathway of apoptosis in the gastrocnemius muscle of Fischer344×Brown Norway rats across the ages of 8, 18, 29 and 37 months, in relation to life-long calorie restriction (CR, 40% calorie intake reduction). Aging caused loss of muscle mass and increased apoptotic DNA fragmentation, which were mitigated by CR. Protein levels of IL-15 and mRNA abundance of IL-15 receptor α-chain decreased in senescent ad libitum (AL) fed rats, but were maintained in CR rodents. Elevations of TNF-α, TNF-receptor 1, cleaved caspase-8 and -3 were observed at advanced age in AL rats. These changes were prevented or mitigated by CR. Our results indicate that aging is associated with decreased IL-15 signaling in rat gastrocnemius muscle, which may contribute to sarcopenia partly through enhanced TNF-α-mediated apoptosis. Preservation of IL-15 signaling by CR may therefore represent a further mechanism contributing to the anti-aging effect of this dietary intervention in skeletal muscle.
sarcopenia; interleukin-15; tumor necrosis factor-α; calorie restriction; apoptosis
Accelerated apoptosis in skeletal muscle is increasingly recognized as a potential mechanism contributing to the development of sarcopenia of aging and disuse muscle atrophy. Given their central role in the regulation of apoptosis, mitochondria are regarded as key players in the pathogenesis of myocyte loss during aging and other atrophying conditions. Oxidative damage to mitochondrial constituents, impaired respiration and altered mitochondrial turnover have been proposed as potential triggering events for mitochondrial apoptotic signaling. In addition, iron accumulation within mitochondria may enhance the susceptibility to apoptosis during the development of sarcopenia and possibly acute muscle atrophy, likely through exacerbation of oxidative stress. Mitochondria can induce myocyte apoptosis via both caspase-dependent and independent pathways, although the apoptogenic mediators involved may be different depending on age, muscle type and specific atrophying conditions. Despite the considerable advances made, additional research is necessary to establish a definite causal link between apoptotic signaling and the development of sarcopenia and acute atrophy. Furthermore, a translational effort is required to determine the role played by apoptosis in the pathogenesis of sarcopenia and disuse-induced muscle loss in human subjects.
Mitochondria; Iron; Sarcopenia; Muscle atrophy; Apoptosis; Caspases; Endonuclease G; Apoptosis-inducing factor
Mitochondria-mediated apoptosis represents a central process driving age-related muscle loss. However, the temporal relation between mitochondrial apoptotic signaling and sarcopenia as well as the regulation of release of pro-apoptotic factors from the mitochondria has not been elucidated. In this study, we investigated mitochondrial apoptotic signaling in skeletal muscle of rats across a wide age range. We also investigated whether mitochondrial-driven apoptosis was accompanied by changes in the expression of Bcl-2 proteins and components of the mitochondrial permeability transition pore (mPTP). Analyses were performed on gastrocnemius muscle of 8-, 18-, 29- and 37- month-old male Fischer344×Brown Norway rats (9 per group). Muscle weight declined progressively with advancing age, concomitant with increased apoptotic DNA fragmentation. Cytosolic and nuclear levels of apoptosis inducing factor (AIF) and endonuclease G (EndoG) increased in old and senescent animals. In contrast, cytosolic levels of cytochrome c were unchanged with age. Mitochondrial Bcl-2, Bax and Bid increased dramatically in 37-month-old rats, with no changes in the Bax/Bcl-2 ratio in any of the age groups. Finally, expression of cyclophilin D was enhanced at very old age. Our findings indicate that the mitochondrial caspase-independent apoptotic pathway may play a more prominent role in skeletal muscle loss than caspase-mediated apoptosis.
sarcopenia; apoptosis; permeability transition pore; AIF; endonuclease G
Muscle atrophy with aging or disuse is associated with deregulated iron homeostasis and increased oxidative stress likely inflicting damage to nucleic acids. Therefore, we investigated RNA and DNA oxidation, and iron homeostasis in gastrocnemius muscles. Disuse atrophy was induced in 6- and 32-month old male Fischer 344/Brown Norway rats by 14 days of hind limb suspension (HS). We show that RNA, but not DNA, oxidative damage increased 85% with age and 36% with HS in aged muscle. Additionally, non-heme iron levels increased 233% with aging and 83% with HS at old age, while staining for free iron was strongest in the smallest fibers. Simultaneously, the mRNA abundance of transferrin receptor-1 decreased by 80% with age and 48% with HS for young animals, while that of the hepcidin regulator hemojuvelin decreased 37% with age, but increased about 44% with disuse, indicating a dysregulation of iron homeostasis favoring increased intracellular free iron in atrophied muscles. RNA and DNA concentrations increased with age and were negatively correlated with muscle mass, whereas protein concentrations decreased with aging, indicating a preferential loss of protein compared to nucleic acids. Furthermore, xanthine oxidase activity increased with age, but not with HS, while mRNA abundance of the Y box-binding protein-1, which has been suggested to bind oxidized RNA, did not change with age or HS. These results suggest that RNA oxidation, possibly mediated by increased non-heme iron, might contribute to muscle atrophy due to disuse particularly in aged muscle.
gastrocnemius; hemojuvelin (HJV); RNA oxidation; sarcopenia; transferrin receptor 1 (TfR1); Y box binding protein 1 (YB-1); xanthine oxidase (XOD)
Endothelial function deteriorates after glucose ingestion. This may be attributed to hyperglycemia-induced oxidative stress. Acute endurance exercise might improve postprandial endothelial function by enhancing glucoregulation and reducing postprandial hyperglycemia.
To determine if endurance exercise performed 17h prior to high-sugar food ingestion attenuates postprandial impairment in endothelial function.
Healthy men and women (n=13; age: 48±17y) were studied on 2 occasions: after ≥48h with no exercise (CON) and 17h after a 60-min bout of endurance exercise (EX). During each trial, brachial artery flow-mediated dilation (FMD) was used to assess endothelial function before and after the ingestion of a candy bar and soft drink. Glucose, insulin, and thiobarbiturate reactive substances (TBARS), as a marker of oxidative stress, were measured in blood obtained during each FMD measurement. Insulin sensitivity index (ISI) was calculated from the glucose and insulin data.
FMD decreased significantly after food ingestion in both trials. However, prior exercise shifted the entire FMD curve upward (main treatment effect: p=0.0002), resulting in a greater area under the curve for FMD (774±122 vs. 607±122 % · min, p=0.01). Prior exercise shifted the glucose and insulin curves downward (main treatment effects: p=0.05 and p=0.0007, respectively) and increased ISI (10.8±0.7 vs. 9.2±0.7, p=0.01). TBARS did not differ between trials.
Postprandial endothelial function was improved by endurance exercise performed ~17 hours earlier. This effect was accompanied by exercise-induced improvements in insulin action and reductions in glycemia but did not correspond with reductions in oxidative stress, as assessed by TBARS.
endothelial function; acute exercise; postprandial; hyperglycemia