Multiple Pathways to the Same End: Mechanisms of Myonuclear Apoptosis in Sarcopenia of Aging

Sarcopenia, the age-related decline in muscle mass and function, represents a significant health issue due to the high prevalence of frailty and disability associated with this condition. Nevertheless, the cellular mechanisms responsible for the loss of muscle mass in old age are still largely unknown. An altered regulation of myocyte apoptosis has recently emerged as a possible contributor to the pathogenesis of sarcopenia. Studies in animal models have shown that the severity of skeletal muscle apoptosis increases over the course of aging and correlates with the degree of muscle mass and strength decline. Several apoptotic pathways are operative in aged muscles, with the mitochondria- and TNF-α-mediated pathways likely being the most relevant to sarcopenia. However, despite the growing number of studies on the subject, a definite mechanistic link between myocyte apoptosis and age-related muscle atrophy has not yet been established. Furthermore, the evidence on the role played by apoptosis in human sarcopenia is still sparse. Clearly, further research is required to better define the involvement of myocyte apoptosis in the pathogenesis of muscle loss at advanced age. This knowledge will likely help in the design of more effective therapeutic strategies to preserve muscle mass into old age, thus fostering independence of the elderly population and reducing the socioeconomic burden associated with sarcopenia

Skeletal Muscle Apoptotic Signaling Predicts Thigh Muscle Volume and Gait Speed in Community-Dwelling Older Persons: An Exploratory Study

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 (R(2) = 0.78; Q(2) = 0.61) as well as gait speed (R(2) = 0.81; Q(2) = 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

Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial-iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA4977) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope (56Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score 64 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores 65 11 (high-functioning, HF). The mtDNA4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability

Determination of quality of life in adolescents with idiopathic scoliosis subjected to conservative treatment.

<p>Abstract</p> <p>Introduction and objectives</p> <p>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.</p> <p>Materials and methods</p> <p>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).</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

Multiple pathways to the same end: mechanisms of myonuclear apoptosis in sarcopenia of aging.

Sarcopenia, the age-related decline in muscle mass and function, represents a significant health issue due to the high prevalence of frailty and disability associated with this condition. Nevertheless, the cellular mechanisms responsible for the loss of muscle mass in old age are still largely unknown. An altered regulation of myocyte apoptosis has recently emerged as a possible contributor to the pathogenesis of sarcopenia. Studies in animal models have shown that the severity of skeletal muscle apoptosis increases over the course of aging and correlates with the degree of muscle mass and strength decline. Several apoptotic pathways are operative in aged muscles, with the mitochondria-and TNF--mediated pathways likely being the most relevant to sarcopenia. However, despite the growing number of studies on the subject, a definite mechanistic link between myocyte apoptosis and age-related muscle atrophy has not yet been established. Furthermore, the evidence on the role played by apoptosis in human sarcopenia is still sparse. Clearly, further research is required to better define the involvement of myocyte apoptosis in the pathogenesis of muscle loss at advanced age. This knowledge will likely help in the design of more effective therapeutic strategies to preserve muscle mass into old age, thus fostering independence of the elderly population and reducing the socioeconomic burden associated with sarcopenia. KEYWORDS: aging, sarcopenia, myonuclear apoptosis, mitochondria, tumor necrosis factoralpha, caspases, endonuclease G, apoptosis inducing factor INTRODUCTION The age-related loss of muscle mass and function, referred to as sarcopenia, is a highly prevalent condition among older persons, affecting 10-25% of the population under the age of 70 years, and over 40% of the individuals aged 80 years or older The socioeconomic burden associated with sarcopenia has instigated intensive research on the factors responsible for this syndrome. Similar to many other age-related conditions, sarcopenia is characterized by a multifactorial etiology, in which neuronal Over the past few years, evidence has accumulated suggesting that an accelerated elimination of myonuclei via an apoptosis-like process might play a significant role in the loss of muscle mass and function with age SIGNALING PATHWAYS OF APOPTOTIC CELL DEATH Apoptosis, a process of programmed cell death, is an evolutionarily conserved, tightly regulated, systematic set of events resulting in cellular self-destruction without inflammation or damage to the surrounding tissue Notably, mitochondria can induce apoptosis via both caspase-mediated and caspase-independent pathways Marzetti et al.: Myonuclear Apoptosis and Muscle Aging TheScientificWorldJOURNAL (2010) 10, 340-349 342 FIGURE 1. Schematic overview of signaling pathways of myonuclear apoptosis activated at advanced age. Aside from their role in cytochrome c-mediated induction of cell death, mitochondria also participate in a pathway of apoptosis that does not involve caspase activation. Endonuclease G (EndoG) and apoptosis inducing factor (AIF) are two mediators that, upon release from mitochondria, translocate to the nucleus and perform DNA fragmentation independent of caspases Upstream of the release of mitochondria-specific apoptotic mediators is the process of mitochondrial outer membrane permeabilization (MOMP) MOMP is also thought to occur via opening of the mitochondrial permeability transition pore (mPTP) THE INVOLVEMENT OF APOPTOSIS IN THE PATHOGENESIS OF SARCOPENIA A wealth of experimental animal data indicates that the apoptotic program is activated in the aged skeletal muscle, likely contributing to the pathogenesis of sarcopenia Given the central role played by mitochondria in the induction and regulation of programmed cell death, intensive investigation has focused on mitochondria-driven myonuclear apoptosis Alteration in the expression of Bcl-2 family proteins has been reported in skeletal muscles of aged experimental animals Besides alterations in the Bcl-2 rheostat, increased susceptibility towards opening of the mPTP has also been demonstrated in aged skeletal muscles Once MOMP has occurred, the release of apoptogenic factors stored in the mitochondrial intermembrane space ensues, initiating the series of events that culminate in cell death These observations have cast doubts about the involvement of mitochondrial caspase-dependent apoptosis in the pathogenesis of sarcopenia. In contrast, several studies have shown that caspaseindependent apoptotic pathways are activated in old age Besides mitochondria-driven apoptosis, other pathways of myonuclear apoptosis have been found to be operative at advanced age. In particular, the death receptor-mediated pathway, triggered by TNF-α, is thought to play a significant role in age-related muscle loss Similar to the TNF-α/IL-15 axis dysfunction, an altered balance between insulin-like growth factor-1 (IGF-1) and TNF-α may also contribute to the proapoptotic environment taking place in the aged muscle. IGF-1, either systemic or muscle derived, is a potent stimulator of muscle development, hypertrophy, and Marzetti et al.: Myonuclear Apoptosis and Muscle Aging TheScientificWorldJOURNAL (2010) 10, 340-349 345 maintenance Other apoptotic pathways that may be operative in the aged muscle include those initiated by caspase-2 and -12; however, their contribution to sarcopenia has yet to be established. Braga et al. Finally, recent evidence suggests that the ER-induced apoptosis may participate to age-related muscle atrophy. In fact, increased caspase-12 expression was detected in the skeletal muscle of old rat

Increased iron content and RNA oxidative damage in skeletal muscle with aging and disuse atrophy. Exp Gerontol 43: 563–570

Keywords: Gastrocnemius Hemojuvelin (HJV) RNA oxidation Sarcopenia Transferrin receptor-1 (TfR1) Y box-binding protein-1 (YB-1) Xanthine oxidase (XOD) a b s t r a c t 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

Relationship between Mitochondrial Quality Control Markers, Lower Extremity Tissue Composition, and Physical Performance in Physically Inactive Older Adults

Altered mitochondrial quality and function in muscle may be involved in age-related physical function decline. The role played by the autophagy–lysosome system, a major component of mitochondrial quality control (MQC), is incompletely understood. This study was undertaken to obtain initial indications on the relationship between autophagy, mitophagy, and lysosomal markers in muscle and measures of physical performance and lower extremity tissue composition in young and older adults. Twenty-three participants were enrolled, nine young (mean age: 24.3 ± 4.3 years) and 14 older adults (mean age: 77.9 ± 6.3 years). Lower extremity tissue composition was quantified volumetrically by magnetic resonance imaging and a tissue composition index was calculated as the ratio between muscle and intermuscular adipose tissue volume. Physical performance in older participants was assessed via the Short Physical Performance Battery (SPPB). Protein levels of the autophagy marker p62, the mitophagy mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), the lysosomal markers transcription factor EB, vacuolar-type ATPase, and lysosomal-associated membrane protein 1 were measured by Western immunoblotting in vastus lateralis muscle biopsies. Older adults had smaller muscle volume and lower tissue composition index than young participants. The protein content of p62 and BNIP3 was higher in older adults. A negative correlation was detected between p62 and BNIP3 and the tissue composition index. p62 and BNIP3 were also related to the performance on the 5-time sit-to-stand test of the SPPB. Our results suggest that an altered expression of markers of the autophagy/mitophagy–lysosomal system is related to deterioration of lower extremity tissue composition and muscle dysfunction. Additional studies are needed to clarify the role of defective MQC in human muscle aging and identify novel biological targets for drug development