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It has been postulated that decreases in muscle fibre size and number are responsible for the observable decrements in muscle mass synonymous with sarcopenia (Narici & Maffuli., 2010). Muscle mass and whole muscle size peak around the age of 25 years old, and are typically well maintained until the fourth and fifth decade of life (Deschenes, 2004). From this point individuals who do not undertake strength and conditioning exercises undergo a 1-2% reduction in muscle mass per year (Lauretani et al., 2003, Marcell, 2003; Hiona & Leeuwenburgh, 2008). Currently debate exists as to whether sarcopenia is a normative process, or whether it is caused by disease and simply exacerbated by disuse (Marcel et al., 2003). Disuse has been shown in the literature to evoke reversible muscle atrophy, however the charterstics of sarcopenia differ from that of disuse as sarcopenia results in both reductions in fibre size as well as in number (Taylor et al., 2004).
3.1. Muscle fibre composition and changes with ageing.
Diminished levels of muscle mass associated with advancing age have been largely attributed to the progressive atrophy and loss of type II fibres (Deschenes, 2004). Research has consistently highlighted that type II muscle fibres are more susceptible to atrophy in comparison to type I muscle fibres (Narici & Maffuli., 2010 ). Research has suggested overall number of muscle fibres are subject to reductions of over 30% in elderly skeletal muscle (Dreyer et al., 2006). Current opinion proposes that the ageing process evokes a loss of both fibre types, but that these decrements occur during different time points (Narici & Maffuli., 2010 ). Type II fibres have been shown to be subject to greater losses in the seventh decade of life, however the eight decade results in substantial reduction in type I fibre levels (Deschenes, 2004). This in essence creates a new balance between the two fibre types, proposing a similar type I/II ratio of muscle fibres for individuals over the age of 85 years old and above (Narci, 2010). Taken together research findings suggest that the relative composition of fibre types can become obfuscated in old age, due to the fact that approximately one third of fibres both co-express MHC-I and MHC-II, they cannot be exclusively categorized (Anderson et al., 2003; Narici & Maffuli., 2010).
Age related alterations in the nervous system can influence the loss of muscle mass which is synonymous with sarcopenia, inducing a reduction in both slow and fast motor units (Marcell, 2003; Taylor et al., 2004; Streeper., 2010). A motor unit consists of a single alpha motor neuron and all of the muscle fibres it innervates (Streeper., 2010). Diminishment of motor units occurs via the process of denervation, resultantly creating a higher work load for the surviving motor units, as a compensatory measure to counteract this imbalance the body produces neural cell adhesion molecules (NCAM), whereby they recruit denervated fibres and attract regenerating axons to the abandoned muscle cells (Terry et al, 2008.) NCAM have been linked to the process of muscle remodeling where fibres are changed to the fibre type of the motor unit, namely a conversion of type II fibres to type I as can be seen in figure 2 (Streeper et al., 2010). Reduction in type II fibres and motor units has a significant impact on the power generating capacity of remaining units, demonstrating a prominent role within the age associated changes in elderly skeletal muscle (Streeper et al., 2010). Declines in skeletal muscle mass are not evenly distributed throughout the body, muscle mass decrements have been documented to be higher in the lower extremities, which may seem counterintuitive given the regular use of lower limbs for locomotion purposes (Baumgartner et al., 1995, Gallagher et al., 2000). Heightened losses experienced by the leg muscles may explain the concurrent loss of mobility observed during ageing, although the underlying cause of this difference has not yet been fully elucidated (Reid, Naumova, Carabello, et al., 2008).
4.0. Etiology of Sarcopenia.
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. TNF-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).
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.
4.2. Anabolic 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).