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The causes and mechanisms responsible for sarcopenia are multifactoral in nature Roubenoff, 2004. Research has highlighted the involvement of central and peripheral nervous system alterations, hormonal, nutritional, immunological and physical activity changes (Meng et al., 2010). Although as of yet the exact mechanisms have not yet been elucidated (Narci et al., 2010). Amongst the various internal processes the most significant contributors are as follows:
The reduction in levels of anabolic hormones (testosterone, estrogens, GH, IGF-1);
Increased levels of pro inflammatory cytokines (esp. TNFÎ‘Î±, IL-6);
Oxidative stress due to accumulation of free radicals;
Mitochondrial dysfunction of muscle cells;
Increased apoptotic activities in the myofibres;
Decline in the number of Î±-motoneurons;
Inadequate dietary intake. Specifically an imbalance and deficiencies in protein intake;
Acute and chronic co-morbidities will also contribute to the development of sarcopenia in older persons.
Each factor distinctly contributes towards sarcopenia, however a complex physiological network exists between anabolic hormones, inflammatory cytokines and the biochemical and molecular pathways (Gordon et al., 2010; Meng et al., 2010). This complex interplay mediates either the respective anabolism or catabolism of muscle protein which can consequentially lead to impairments within physical function (Newman et al., 2008; Meng et al., 2010). Muscle mass and strength are central contributors towards physical independence and can potentially decreases both the occurrence of skeletal fractures, and the detrimental effects which fractures pose (Binder et al., 2004; Delmonico et al., 2006). In conceptualizing the importance of muscle mass and strength with advancing age, it must be noted that these two parameters are subject to heightened decrements as a result of sarcopenia (Marini & Veicsteinas., 2010).
2.4.1. Insulin like growth factor- 1.
Insulin like growth factor 1 (IGF-1) has received extensive attention in the research literature, highlighted as possibly the most important mediator of muscle growth and repair (Goldspink., 2007). IGF-1 is a central contributor in the governance of cell growth, survival and differentiation in several tissues (Chesik et al., 2007). Although most organs and cell types synthesize IGF-1, circulating IGF-1 is predominately produced by the liver (Goldspink., 2007). IGF-1 can also be synthesized as a result of growth hormone (GH) secretion from the anterior pituitary gland (Doughday., 2000; Hameed et al., 2002). However in skeletal muscle local IGF-1 expression has been documented to be GH independent (Goldspink., 2007). Research has elucidated that IGF-1 can also be produced locally, possessing the ability to be synthesized in the same cell which it acts (autocrine) or in neighbouring cells (paracrine), as can be seen in figure 4 (Gomes, 2009). As a hormone IGF-1 is unique in the sense that it is controlled by a family of 6 binding proteins which can both inhibit and stimulate IGF-1 action (Nindl, 2010). The biological activity of IGF-1 is determined by the amount of unbound, free IGF that is locally available for binding to IGF-1 receptors (Nindl., 2010). Although there is an 80% sequence homology between the genes of the six IGFBPs, each IGFBP exhibits unique properties and is expressed in a tissue dependent manner (Ferry et al., 1999, Chesik et al., 2007)., however IGFBP-3 has been shown to carry 90% of the IGFs in circulation bound by IGFBPs (Ferry, Katz, Grimberg, Cohen & Weinzimer., 1999). GH, insulin, and insulin-like growth factors are all hormones important in the regulation of IGFBP3 expression (Alway et al., 2002; Spangenburg et al. 2003
FigureÂ 4 Simplified diagram of GH/IGF-1 axis involving hypophysiotropic hormones controlling pituitary Growth Hormone (GH) release, IGF-1 production in the liver and elsewhere, and tissue responsiveness to GH and IGF-1. GH increases fat mobilization, decreases body fat and decreases adipocyte size and lipid content. Arrows denote stimulation (+) or inhibition (-). SRIF, somatotropin release-inhibiting factor; GHRH, GH-releasing hormone (Gomes et al., 2009).
IGF-1 is a focal in the maintenance of skeletal muscle mass and neuronal function, exerting potent anabolic actions in several tissues including the bone (Di Monaco, 2009). Lower levels of circulating IGF-1, have been highlighted as a causative factor within the age associated declines in muscle function (Goldspink., 2007). IGF-1 exerts its hypertrophic effects by promoting a net increase in protein content, demonstrating a strong relationship with muscle mass and strength through its respective binding to Akt and impact on protein synthesis (Cappola et al., 2001; Manini et al., 2005; Goldspink et al., 2007; Moran et al., 2007). With advancing age IGF-1 levels are amenable to decrements, but this is subject to a high degree of variability among individuals (Goldspink, 2007). As part of the Baltimore Hip Studies (BHS-3) it was demonstrated that serum IGF-1 levels varied between 12.8 to 461.3 Âµg/litre among elderly women (Cappola et al., 2001; Cappola et al., 2010). The Women's Health and Ageing Study I (WHAS I), revealed that following a hip fracture elderly women displayed significant lower levels of IGF-1 for both the first and second year preceding their subsequent hip fracture. This attribution has been well established and replicated within the research literature, correspondingly in the Os des Femmes de Lyon (OFELY) study, IGF-1 levels which fell below median values were associated with a threefold increase in fracture risk (Garnero et al., 2000). Chagnon et al., (2001) performed a genome-wide search for genes related to body composition and its changes after a 20-wk exercise training program, evidence of significant linkage with changes in fat free mass and the IGF-1 gene was uncovered.
2.4.2. Sex hormones- Estrogen.
The term 'estrogens' describes a group of 18-carbon corticosteroid molecules secreted primarily by the ovaries in females and, to a lesser extent, by the testes in males (Kendall & Eston., 2002). Three major naturally occurring estrogens exist in women, these are estrone (E1), estraidiol (E2), and estriol (E3) (Maltis, 2009). Women who go through the menopause experience lower levels of circulating estraidiol (Maddalozzo et al., 2004), during this stage of life females experience impairments in muscle function which appear to be in parallel with the reductions in the synthesis of ovarian hormones (Fanciulli, et al., 2009). It has been proposed that women experience an accelerated loss of muscle mass and strength at an earlier age than men, rapid decrements are believed to occur around the time of menopause, theoretically making them weaker at 65-69 years old in comparison to men aged 85-89 years old (Maltis, 2009). Attenuated production of estrogen contributes to the reduction in bone mineral density, the redistribution of subcutaneous fat to the visceral area and also decrements in quality of life (Enns & Tiidus., 2010; Messier et al., 2010). Data from the New Mexico elderly study, found prevalence rates of sarcopenia to be approximately 23.6% in healthy independent postmenopausal women (<70 years old) in comparison to 15.4% in men (<70 years old) (Baumgartner et al 2002).
Whereas age associated reductions in muscle mass and strength have been extensively documented in the research literature, it is extremely difficult to disentangle the relative contribution of menopause towards this process, irrespective of the changes observed as a result of biological ageing (Enns & Tiidus., 2010). To further complicate matters several factors contribute towards the loss of muscle mass such as physical activity, inflammatory factors, leg strength and power and BMI each of which are also concurrently related to age and menopause status (Enns & Tiidus., 2010; Messier et al., 2010). Current knowledge into the relationship between sex hormones and muscle strength in women is both weak and inconclusive in comparison to knowledge relating to the mechanisms explaining lower testosterone levels and muscle strength (Maggio et al., 2006). An emerging mechanism which has been linked as the underlying cause to explain estrogens effect on muscle strength has been the actions of estrogen receptors (ER), shown to evoke positive effects within the function of myosin (Lowe , 2010). Estrogen receptors have been demonstrated to be present in human muscles especially on type II muscle fibres, which has significant relevance to the current study population (Baltgalvis et al., 2010). Although the roles of estrogen receptors are not yet fully elucidated, it is believed that they contribute to both the synthesis of muscle tissue at rest and the repair process of muscle fibres which occurs after exercise (Joseph et al., 2005). Estrogen receptors have a dependent relationship with circulating estrogen but they have been also shown to be activated by IGF-1, which can activate and promote the transcriptional activity of estrogen receptors. Consequently estrogen receptors may exert their effects of muscle strength not only through direct activation of estrogen but additionally via IGF-1 (Baltgalvis et al., 2010; Pollanen et al., 2010; Athianen et al., 2011).
2.4.3. Increased levels of pro inflammatory cytokines (TNFÎ‘Î±, IL-6).
Following the establishment of a central role for chronic inflammation in the pathogenesis of several age related diseases, clinicians and researchers have been encouraged to focus their attention towards the role which inflammatory markers play in the progression of sarcopenia (Yu & Chung., 2006). Cytokines are small non-structural proteins, or glycoproteins which function as chemical messengers between cells (Zoico, 2002). On a biochemical level cytokine communication is mediated following their binding to specific receptors on the surface of target cells, this in turn sends a signal to the nucleus to induce transcription of a specific set of genes exerting their effect (Roubenoff, 2003). Predominately cytokines are involved in the initiation and regulation of the acute phase inflammatory response, although recent evidence has elucidated their involvement in a variety of physiological processes such as cell growth and differentiation, tissue repair and remodelling (Yu & Chung., 2006). Cytokines have the ability to exert both anabolic and catabolic functions in skeletal muscle cells, exerting their effects on muscle homeostasis but also playing a role in disease pathogenesis (Roubenoff, 2003; Morley et al., 2004). The catabolic effect which pro inflammatory cytokines such as TNFÎ±, IL-1, and IL-6 pose to skeletal muscle fibres has been demonstrated both in vitro and in vivo (Visser et al., 2002; Schrager, Bandinelli, Maggi & Ferrucci., 2003).
Interleukin-6 (IL-6) was one of the first cytokines to be linked to the ageing process, and has since been termed the ''cytokine for geriatricians'' (Ershler & Keller., 2000). One of the main functions of IL-6 is self-limiting the inflammatory response, promoting the expansion and activation of T cells and differentiation of B cells (Pedersen et al., 2006). IL-6 plays a role in the development of inflammation, which raises the question of whether the elevated levels of IL-6 which are consistently observed in frailty are an attempt to rectify an inflammatory response (Maggio et al., 2006). TNFÎ± and Interleukin-1 beta (IL-1Î²) have been identified as potent releasers of IL-6. Following its release IL-6 feeds back to down regulate the release of both TNFÎ± and IL-1Î² giving IL-6 the ability to perform both anti-inflammatory, as well as proinflammatory roles (Roubenoff, 2003; Morley et al., 2004: Gleeson et al., 2011). Respective properties and capabilities of TNFÎ± have been shown to be multifaceted, it is known TNFÎ± can induce apoptosis, chronic inflammation and cachexia systemically (Beutler et al, 1988; Maggio et al., 2006). On a molecular level TNFÎ± has also been implicated as an important mediator in the activation of the Nuclear Factor Kappa Î² pathway, which holds particular significance to the studied population as NF-KB has been heavily implicated in osteoporosis and fracture risk (Morley et al., 2004; Meng et al., 2010).
IL-6 has been shown to exert low grade catabolic effects on skeletal muscle, postulating that over time this may induce a negative protein balance, resulting in reduced strength ultimately leading to sarcopenia (Roubenoff, 2003; Doherty, 2003; Jenseen, 2008; Chung et al., 2009). High concentrations of IL-6 have been shown to be associated with movement disabilities, slower walking speed, and lower grip strength (Ferruci et al, 2002; Ceserria et al., 2004). Leng et al, (2004) displayed an inverse correlation between IGF-I and IL-6 in frail, but not in non frail older people. Lending support to a possible endocrine dysregulation specific to this population. Additionally as mentioned previously low levels of IGF-1 along with high levels of IL-6 were separate and in certain instances interrelated risk factors for disability in both the Women's Health and Ageing Study 1 (Cappola et al. 2003) and the InCHIANTI study (Barbieri et al. 2003). Evidentially, a complex physiological interplay exists between various anabolic hormones (growth hormone, IGF-1 and testosterone), inflammatory cytokines (IL-6, TNFÎ±), along with biochemical and molecular pathways in the catabolism of muscle protein (Meng et al., 2010). Ascertaining the effects which exercise poses on muscle and plasma levels of TNFÎ‘Î± and IL-6, is of interest due to its potential role as a therapeutic method to reduce systemic inflammation (Gleeson et al., 2011).
2.4.4. Protein metabolism.
Muscle represents the largest tissue in the body, accumulatively 25% of all protein synthesis taking place in the body occurs in skeletal muscle (Morley et al, 2001). Retrospectively a decreased supply of amino acids from the diet, or an elevated demand for amino acids from catabolic process will ultimately contribute to increased protein degradation from the muscle (Buford et al., 2010). The number of skeletal muscle cells, which reflects the balance of cellular turnover is believed to remain relatively constant until adulthood, however this is subject to vast changes with advancing age (Narci et al., 2010). Contrastingly the size of muscle cells which reflects the balance of protein turnover (protein synthesis and degradation) is receptive to a number of conditions (Lang & Castaneda, 2009). These include ageing, physical activity, hormones, growth factors, nutrition, mechanical stress and diseases are factors that influence muscle size via the regulation of protein synthesis and degradation pathways (Dreyer & Volpi, 2005). Rates of protein synthesis in skeletal muscle decline with advancing age, these changes may potentially increase elderly individual's vulnerability and susceptibly to conditions such as sarcopenia, frailty, metabolic syndrome and other co morbidities (Marcell, 2003; Narci, 2010). Skeletal muscle mass is an extremely important tissue representing the largest reservoir of protein in the body (Dreyer & Volpi, 2005). The dynamics of human skeletal muscle requires an ongoing balance between the processes of protein synthesis and breakdown. The intricate process of protein metabolism determines either the anabolic or catabolic state of a tissue, via the residual equilibrium between the two states as can be seen in figure 5 (Lang & Castaneda, 2009). Small imbalances and deficits between these processes over time can result in levels of muscle mass loss similar to those observed as a result of the ageing process (Marcell, 2003;Narci, 2010). As can be seen in figure 5 many factors are involved in the process of protein metabolism.
Research has often ascribed to the premise that the age associated changes observed in muscle size and strength may be consequential effects of lower protein turnover in ageing muscle (Narci et al., 2010).
Several studies have shown that the synthesis of mixed muscle protein (MMP) which includes myofibrillar and mitochondrial proteins is reduced by about 30% with age (Welle et al., 1993; Welle et al., 1995; Balagopal et al., 1997). The synthetic rate of mixed myofibrillar proteins which includes contractile proteins, such as myosin heavy chain (MHC) are significantly reduced in older individuals (Wilborn & Willoughby, 2004). It is important to note that the synthesis of MHC is positively correlated with muscle mass and strength not MMP (Short & Nair, 1999). The strong relationship between muscle MHC synthesis rate and muscle strength, reiterates the ideal that muscle contractile function is at least partly determined by the ability to produce the necessary proteins (Balagopal et al., 1997). A plausible explanation for the age associated decrements observed in protein synthesis can be found in the observed reductions in the amount of mRNA available for translation of the protein (Balagopal et al., 2001). Research has shown that elderly individuals demonstrate declines not only in the capacity (which is essentially the ratio of RNA to total protein), but also in the efficiency of skeletal muscle protein synthesis (Kim, Wlison, Lee, 2010). However elderly individuals have been highlighted as displaying signs of a blunted response to anabolic stimuli (Narci, 2010).
2.4.5. Reactive Oxygen Species.
The role which reactive oxygen species (ROS) plays in the ageing process has been subject to intensive research, its affirmative role has long been accepted among scientists (Meng et al., 2010). With advancing age, increases in oxidative stress are often observed (Mc Ardle & Jackson, 2011). This relationship has been attributed to the imbalance between the two infinite processes of free radical production and antioxidant defences with marked elevation in the former (Sastre et al., 2000). An ideal "golden triangle" of oxidative balance, in which oxidants, antioxidants and biomolecules are placed at each apex, has been described to illustrate this process (Carmeli et al., 2002). In a normal situation, a balanced-equilibrium exists among these three elements, excess generation of free radicals may overwhelm natural cellular antioxidant defences leading to oxidation and further contributing to cellular functional impairment (Bowles et al., 1991; Meydani et al., 1993). In its simplest terms a free radical is a molecule with an unpaired electron, reactive Oxygen Species (ROS) is a collective term for oxygen-derived molecular species (Afzal & Armstrong, 2002). Thus, this term includes free radical species, in addition to species that have paired electrons but are capable of becoming involved in harmful reactions that cause damage to other biomolecules (e. g. hydrogen peroxide) (Halliwell & Gutteridge, 1999). Environments of high oxidative stress can be generated as a result of an overproduction of specific ROS and/or decrements in the effectiveness of the antioxidants ability to quench them (Powers & Jackson, 2008). ROS are more commonly associated with negative effects on tissue homeostasis, however evidence is accruing that the role of ROS is not solely restricted as being damageing agents (Meng el al., 2010; Mc Ardle & Jackson, 2011). ROS possesses the ability to act as messengers within cellular signal transduction pathways, which regulate both normal physiological signalling and pathological signalling (Ji, 2007). ROS generated during physical exercise modify intracellular oxidant-antioxidant homeostasis, possibly impacting on the ageing process (Powers & Jackson., 2008). Clear evidence suggests that an acute bout of heavy intensive exercise generates sufficient ROS to challenge the body's antioxidant defence system (Powers & Jackson., 2008; Mc Ardle & Jackson, 2011), a pertinent issue for the chosen study population in terms of exercise prescription. Despite heightened knowledge within the area, many unanswered questions still exist. These are in relation to the involvement of the benefits associated with exercise, that if exercise generates free radicals and causes oxidative damage how much is good for you when you get older and do older people who are physically active need to take an antioxidant supplementation (Ji et al., 2009).
Figure 6- The diagram below demonstrates with specific emphasis on oxidative stress that whereas each factor contributes towards sarcopenia in its own way, a complex network exists and is very much inter related. Demonstrating that the maintenance of skeletal muscle mass is largely dependent upon a number of tightly regulated process governing muscle protein synthesis, protein degradation as well as cell regeneration (Adapted from Meng et al., 2010).
2.4.6. Mitochondrial dysfunction.
Since the introduction of the 'Free Radical Theory of Ageing' by Harman over 50 years ago, oxidants have been inextricably linked to ageing (Harman,1956). The basic underpinnings of this theory propose that cumulative damage to biological macromolecules caused by oxygen radicals (ROS) induces irreversible cell damage, which subsequently leads to declines in functional ability (Harman, 1956; Jackson et al., 2008). Advances in the area have extended the theory to include mitochondria, its inclusion has been justified by the demonstration that the age associated mitochondrial DNA (mtDNA) accumulation and deletions have negative and counterproductive effects on the function of the respiratory chain which augment ROS production (Chomyn & Attardi., 2003). Enhanced ROS production can result in the commencement of a vicious cycle of exponentially increasing levels of mtDNA damage and oxidative stress in the cell (Kujoth et al., 2006; Seo et al., 2006; Hiona & Leeuwenburgh, 2008; Seo et al., 2008). Advancing age is associated with decrements in mitochondrial turnover due to reductions in mitochondrial biogenesis and/or inefficient mitochondrial degradation, contributing towards the ageing process (Terman et al., 2010). Mitochondria is a major site for the production of free radicals as by products. In mammals, mitochondria encode 37 genes: 13 for proteins (polypeptides), 22 for transfer RNA (tRNA) and one each for the small and large 39 subunits of ribosomal RNA (rRNA) (Puigserver et al., 1998; Wu et al., 1999; Lehman et al., 2000). Mitochondrial DNA (mtDNA) in comparison to nuclear DNA is extremely susceptible to damage by ROS, due to reduced levels of protective histones, relative deficiencies in repair mechanism and the proximity of mtDNA to the source of ROS- the inner mitochondrial membrane (Cadenas et al., 2000). Preservation of mtDNA is essential for normal cellular function, as it encodes both proteins required for oxidative phosphoryaltion and ATP synthesis (Wallace & Fan, 2009). Age associated mtDNA modifications and mutations resultantly interferes with the synthesis of protein and the enzymatic pathways, which are responsible for the transfer of electrons along the respiratory chain as well as ATP (Hiona et al., 2008). Wallace & Fan, (2009) postulated that whereas mutations in accumulate over time, that it is when a critical threshold is reached (~70-90% of total mtDNA) where clinical symptoms will present themselves. Whereas the mechanistic underpinnings are not yet fully elucidated, current knowledge in the area would suggest that these are multifactoral (Wallace & Fan, 2009).
2.4.7. Physical activity.
Over the years interest towards the effects of physical activity on the ageing process has increased. Considering the trends of increased longevity it is important to establish the degree to which physical activity can improve the various aspects of health and well being in this population and the mechanisms responsible for the changes and understand what type of exercise is most beneficial (Booth et al. 2000; Taylor et al., 2004). The 21st century has seen the adoption of lifestyles and behaviours which have almost eradicated opportunities for spontaneous physical activity, so much so that people are neglecting its importance and for health and well being. Amidst the array of physiological changes which occur as a result of the ageing process, decrements are observed in aerobic capacity estimated as peak oxygen consumption (V02max) (5-10% per decade in untrained individuals) coupled with reductions in muscle mass tissue (Daley & Spinks, 2000). Together this can accumulatively result in diminished muscle mass and strength, which is of fundamental importance to current study populations. Individual's ability to function independently depends largely on maintenance of sufficient aerobic capacity and muscle strength to carry out daily tasks can be increased and maintained through physical activity (Taylor et al., 2004).
Older populations are an unique subset with characteristics and behaviours, which make the task of healthy ageing more challenging (Binder et al., 2004). Amongst the ever increasing list of benefits associated with physical activity bone and muscle health remain close to the top, exercise has demonstrated the ability to improve muscle strength and simultaneously enhance bone architecture and fracture resistance (Binder et al., 2004; Taylor et al., 2004). This has particular relevance to the current study population. Analysis of data from the Sport and Physical Activity Survey suggests that overall 42.7% of adults in Northern Ireland meet the current physical activity guidelines. This is above levels recently reported (34%) from the Health Survey for England (Bélanger et al., 2011). However when the data is broken down into broken down into age quintiles as can be seen below only 26.34 % of adults over 60 years old were achieving >150 minutes of moderate to vigorous physical activity per week. The proportion of individuals walking declined with age with less than 47% of participants aged 71+ years reporting walking 10 minutes or more (Murphy, Donnelly, Shibli, Foster & Nevill, 2012).