Body Composition and Aging

C. V. Mobbs, P. R. Hof

• Editore: S. Karger
• Anno: 2010
• ISBN:
  9783805595223
• Argomento: Medicina
• Categoria: Endocrinologia e metabolismo

Increased adiposity and decreased muscle mass contribute substantially to age-dependent disease and disability. In particular age-related increase in adiposity is quickly becoming a major threat to public health throughout the world. Although the hypothesis that age-related changes in body composition are due to lifestyle choices alone is well accepted, it is a vast oversimplification. This volume reflects the current knowledge in this rapidly developing field of research. The first part of the book discusses the extent to which increased adiposity contributes to age-related diseases and longevity. The 'obesity paradox', describing the protective role of overweight in decreasing mortality while increasing pathology, is covered in depth. Further chapters address specific aspects of the regulation of energy balance during aging, including the effects of changes in food intake. Finally the causes and consequences of loss of muscle mass and age-related osteoporosis are examined.A valuable help for physicians treating elderly patients, this book will also be of great interest to researchers studying energy balance, muscle physiology, bone disease, and other aspects of aging.

Mobbs CV, Hof PR (eds): Body Composition and Aging.
Interdiscipl Top Gerontol. Basel, Karger, 2010, vol 37, pp 115-141

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mTOR Signaling as a Target of Amino Acid Treatment of the Age-Related Sarcopenia

Giuseppe D’Antona^a · Enzo Nisoli^b

^aDepartment of Physiology, Human Physiology Unit and Interuniversity Institute of Myology, University of Pavia, Pavia, and ^bDepartment of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy

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Abstract

Sarcopenia is an age-related structural and functional impairment of skeletal muscle leading to loss of strength, contractile capacity and endurance. Among factors implicated in sarcopenia, deregulation of muscle protein synthesis (MPS) has frequently been reported. Thus, the attempts aiming at identifying possible countermeasures to sarcopenia require consideration of a complex coordinated interaction of factors contributing to the balance between protein synthesis and breakdown and the identification of several regulators on their function. We will focus here on the signaling pathways controlling protein synthesis in skeletal muscle, specifically on one of the downstream effectors of the kinase Akt/PKB, the mammalian target of rapamycin (mTOR) kinase which is now recognized as a key regulator of cell growth and a pivotal sensor of nutritional status over the lifespan. Dysfunction of mTOR signaling in the elderly and its potential role as a target of amino acids in the treatment of age-related sarcopenia will be discussed.

Copyright © 2010 S. Karger AG, Basel

Skeletal muscle represents up to 45% of body weight of adult humans [1] and for its mass to be stable strictly depends on equal rates of protein synthesis and breakdown. Under physiological conditions, continuous protein turnover is a basic cellular process that serves to maintain the conservation of cytoplasm content and cell size and to provide amino acids for oxidative and biosynthetic reactions. As a direct consequence, the balance between new protein formation (synthesis) and catabolism (breakdown) determines the overall protein content within each muscle fiber [2]. The synthetic rates of the two major myofibrillar proteins (i.e. myosin and actin) and the noncontractile proteins, including sarcoplasmic proteins and others, have been extensively investigated in several species and in numerous conditions [3–6]. In healthy adult humans, rates of myofibrillar protein synthesis have been calculated (around 0.8 g day^–1 kg^–1) [4] and the mean daily turnover rate has been expressed as a fraction of the total body protein turnover, which ranges in different studies from less than 1% to more than 2% [4–6], without differences between men and women [5,7,8]. This fraction, which appears to be much higher during development (more than 3% in newborns and 5% in premature newborns) [9–11], is an index of muscle growth [10] and correlates with the age-related increase in fiber size. In particular, the protein synthetic rates and muscle growth are positively related during the period of life in which muscle weight is proportional to body weight [10], while this positive relationship appears to be lost in presence of quantitative reduction of skeletal muscle mass (atrophy). This loss physiologically occurs in healthy aging, and is known as sarcopenia, which is defined in humans by appendicular skeletal muscle mass per height² (<7.26 kg m^–2 for males and <5.45 kg m^–2 for females) [12,13]. In fact, in the presence of sarcopenia, which is responsible for unequal loss of muscle mass and force generation [14,15], increased prevalence of falls and fractures, greater morbidity and loss of autonomy in the elderly is associated with lower myofibrillar protein turnover and reduced protein synthesis, increased protein degradation, or a combination of both [16]. Furthermore, a clear unbalance between protein synthesis and breakdown appears as the leitmotif of aging and several other conditions leading to severe muscle wasting, including uncontrolled metabolic disorders (diabetes) [7,17], denervation [7,18], atrophic myopathies [19], dystrophies [9,20], sepsis [21–24] and cancer [25–27]. Considering the shared endpoint of different atrophic conditions, common mechanisms able to affect synthesis and/or degradation might exist and several coexisting regulatory factors such as hormones (growth hormone, insulin-like growth factor-1 or IGF-1, insulin, testosterone, glucocorticoids, thyroxine), nutritional status (amino acids availability), and the basal level of physical activity [15,28] may have differential impact on metabolic balance. In any case several lines of evidence suggest that muscle atrophy, and thus sarcopenia, is not the simple converse of hypertrophy [29], and distinct pathways and unique set of genes are differentially activated [30,31]. The onset of skeletal muscle atrophy is strictly related to the activation of the ATP-dependent ubiquitin-proteasome pathway [32] and follows the increased levels of mRNAs encoding for essential components of the ubiquitin-proteasome machinery [31,32]. The inhibition of this pathway decreases protein breakdown in skeletal muscles, thus preventing proteolysis [33]. Furthermore, in experiments to identify specific markers of muscle wasting, two genes, atrogin-1/MAFbx and MuRF1, appeared significantly upregulated before the onset of mass loss in different models of muscle atrophy. These genes encode for muscle-specific ubiquitin ligases responsible for substrate specificity during protein degradation through the ubiquitin-proteasome pathway [34–36]. The demonstration that ablation of either gene results in protection against denervation-induced atrophy, highlights the relevance of these two ligases in the onset of skeletal muscle atrophy [34].

On the other hand, in the presence of physiological conditions promoting muscle growth, a major role in controlling the cellular hypertrophic response has to be attributed to the activation of PI3K-Akt signaling pathway due to an increased expression of IGF-1. IGF-1, the best characterized muscle growth factor, is synthesized in the liver and, locally, in the skeletal muscle [37] where its overexpression in transgenic mice results in fiber hypertrophy [38,39]. Muscle expression of IGF-1 has been found to increase following compensatory overload [40,41]. The bulk of evidence supports the crucial role of protein kinase B (Akt/PKB) pathway in the regulation of fiber size. The acute activation of Akt/PKB kinase promotes highly significant fiber hypertrophy in vivo [42] whereas decreased ability to activate Akt/PKB is coupled with atrophy [43].

The recent identification of a family of transcription factors, the Forkhead box O (FoxOs), negatively targeted by Akt/PKB has opened new vistas on the coordinated response of different signaling pathways controlling atrophy and hypertrophy [44,45]. In particular, Akt/PKB promotes FoxO phosphorylation followed by its translocation from the nucleus to the cytoplasm. The inverse translocation of FoxO, from the cytoplasm to the nucleus, is necessary for upregulation of atrogin-1/MAFbx and MuRF1 [44] and this mediates the development of atrophy. Activation of the PI3K/ Akt pathway by IGF-1 prevents muscle loss through suppression of atrogin-1/MAFbx and MuRF1 expression following inactivation of FoxO [44]. In contrast, in presence of atrophy, reducing FoxO expression by RNAi prevents atrogin-1/MAFbx upregulation [44]. These findings highlight the existence of synergic responses of cellular mediators of hypertrophy and atrophy to a stimulus, such as the local increase/decrease of IGF-1 in skeletal muscle, and suggest future intriguing directions of research. In particular, attempts to identify possible countermeasures to atrophy/sarcopenia of aging [15,46–48] require consideration of a complex coordination of factors contributing to the control of cell size and the impact of several regulators on their function. We will focus here on the signaling pathways controlling protein synthesis in skeletal muscle, specifically on one of the downstream effectors of the Akt/PKB, the mammalian target of rapamycin (mTOR) kinase which is now recognized as a key regulator of cell growth and a pivotal sensor of nutritional status over the lifespan. The role of mTOR as a potential target of amino acids and its possible involvement in amino acid-induced improvement of age-related sarcopenia will be discussed.

Intracellular Mechanisms of Protein Synthesis Regulation: mTOR as a Downstream Target of PKB/Akt

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