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

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

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