336 D.A. Rivas and R.A. Fielding 2007, the American College of Sports Medicine (ACSM)/American Heart Association (AHA) released a joint recommendation on physical activity and pub- lic health recommendations for older adults, the Department of Health and Human Services (DHHS)/Center for Disease Control (CDC) released the “2008 Physical Activity Guidelines for Americans” and in 2009 the ACSM updated and expanded their position stand on “Exercise and Physical Activity for Older Adults”. These recommendations and guidelines affirm that regular physical activity reduces the risk of many adverse health outcomes and there are additional benefits as the amount of physical activity increases with higher intensity, greater frequency and/ or longer duration (see Table 1). 3 Mechanisms of Muscle Atrophy Associated with Sarcopenia 3.1 Protein Synthesis and Degradation The maintenance of muscle mass is regulated by a balance between protein synthe- sis and protein degradation and is associated with rates of anabolic and catabolic processes, respectively. In conditions of atrophy, there is evidence for a shift toward myofibrillar and non-myofibrillar protein degradation (Mitch and Goldberg 1996) and a corresponding reduction in protein synthesis (Munoz et al. 1993). When protein synthesis exceeds protein degradation there is increased muscle mass (hypertrophy). In contrast, if protein degradation exceeds protein synthesis there is muscle loss (atrophy). During muscle atrophy as a result of disease processes, dis- use or aging there is a preferential degradation of intermittently used white muscle (Type 2) fibers rather than continually used red muscle (Type 1) fibers (Tomlinson et al. 1969; Larsson 1983; Aniansson et al. 1986). Lexell et al. (1988), when study- ing 15–83 year old previously healthy men, reported that after the age of 25 years there is both a loss in the number and size of muscle fibers (Lexell et al. 1988). These researchers concluded that the fiber size reduction can be explained mostly by the smaller Type 2 fibers. However, it has been recently reported that there is a disproportionate loss of muscle function relative to muscle loss (Goodpaster et al. 2006; Haus et al. 2007). Therefore, the loss of muscle mass during aging could be the result in a decline of protein synthesis, increase in protein degradation or a combination of both. There is some contention regarding whether the decrease in protein synthesis associated with aging occurs solely during anabolic stimulation (Volpi et al. 2001; Cuthbertson et al. 2005; Rennie 2009) or also in the basal state (Nair 1995; Welle et al. 1993; Rooyackers et al. 1996; Yarasheski et al. 1993). It was originally reported that old subjects had decreased rates of basal muscle protein synthesis (Rooyackers et al. 1996; Yarasheski et al. 1993; Welle et al. 1993). However, others have been unable to reproduce these results and have observed a decrease only during anabolic stimulation (Rennie 2009; Volpi et al. 2001; Cuthbertson et al. 2005). 337Exercise as a Countermeasure for Sarcopenia The concept of aging is also strongly associated with increased protein degradation leading to muscle atrophy. The effects of aging on protein degradation are difficult to quantify. This is because in adult humans and animals only 60–70% of skeletal muscle proteins are made up of myofibrillar protein and these turn over very slowly making their quantification very difficult [see review: (Attaix et al. 2005)]. Table 1 Summary of physical activity recommendations for older adults from the American College of Sports Medicine/American Heart Association and the U.S. Centers for Disease Control and Prevention/ Department of Health and Human Services (Adapted from Nelson et al. 2007; Chodzko-Zajko et al. 2009; DHHS 2008) ACSM/AHA Physical activity recommendations for older adults: Aerobic exercise: Frequency: For moderate-intensity activities, accumulate at least 30 or up to 60 (for greater benefit) min/day in bouts of at least 10 min each to total 150–300 min/week, at least 20–30 min/day or more of vigorous-intensity activities to total 75–150 min/week, an equivalent combination of moderate and vigorous activity. Intensity: On a scale of 0–10 for level of physical exertion, 5–6 for moderate-intensity and 7–8 for vigorous intensity. Duration: For moderate-intensity activities, accumulate at least 30 min/day in bouts of at least 10 min each or at least 20 min/day of continuous activity for vigorous-intensity activities. Type: Any modality that does not impose excessive orthopedic stress; walking is the most common type of activity. Aquatic exercise and stationary cycle exercise may be advantageous for those with limited tolerance for weight bearing activity. Strength exercise: Frequency: At least 2 days/week. Intensity: Between moderate- (5–6) and vigorous- (7–8) intensity on a scale of 0–10. Type: Progressive weight training program or weight bearing calisthenics (eight to ten exercises involving the major muscle groups of 8–12 repetitions each), stair climbing, and other strengthening activities that use the major muscle groups. Flexibility exercise: Frequency: At least 2 days/week. Intensity: Moderate (5–6) intensity on a scale of 0–10. Type: Any activities that maintain or increase flexibility using sustained stretches for each major muscle group and static rather than ballistic movements. Balance exercise: recommended for frequent fallers or individuals with mobility problems. CDC/DHHS Physical activity recommendations for older adults: All adults should avoid inactivity. Some physical activity is better than none, and adults who participate in any amount of physical activity gain some health benefits. Aerobic exercise: Frequency: For moderate-intensity exercise, perform 30 min/day for 5 days/week or vigorous- intensity exercise, perform 20 min/day for 3 days/week. You can do moderate- or vigorous- intensity aerobic activity, or a mix of the two each week. Intensity: On a scale of 0–10 for level of physical exertion, 5–6 for moderate-intensity and 7–8 for vigorous intensity. Duration: For moderate-intensity activities, accumulate at least 30 min/day in bouts of at least 10 min each. Strength exercise: Frequency: Ten strength-training exercises, 10–15 repetitions of each exercise 2–3/week. Balance exercises: perform if at risk of falling. 338 D.A. Rivas and R.A. Fielding In keeping with this idea, Volpi et al. (2001) were only able to observe a small increase in basal protein degradation in old versus young humans (Volpi et al. 2001). There are three known major proteolytic pathways that are revealed to have a role in skeletal muscle: the lysosomal pathway, the Ca 2+ -dependent pathway com- prising the m− and m-calpains, and the ubiquitin-proteasome dependent proteolytic pathway (Attaix et al. 2005). Of these, the pathway that has recently received the most interest is the ubiquitin-proteasome pathway. In skeletal muscle this pathway is involved in the breakdown of long-lived myofibrillar proteins. In a variety of conditions such as cancer, diabetes, denervation, disuse, and fasting, skeletal mus- cles atrophy through degradation of myofibrillar proteins via the ubiquitin–protea- some pathway (Edstrom et al. 2006; Attaix et al. 2005; Cao et al. 2005). The induction of the muscle-specific ubiquitin E3-ligases (atrophy gene-1/muscle atro- phy F-box (Atrogin-1/MAFbx) and muscle ring-finger protein 1 (MuRF1)) are thought to be the common mechanism associated with these diseases (Cao et al. 2005). The roles of Atrogin-1 and MuRF-1 in aging related muscle loss are not as clear cut. For example, some studies reported a small increase (Pattison et al. 2003), no change (Welle et al. 2003) or even a downregulation of Atrogin-1 and MuRF-1 mRNA in aged muscle (Edstrom et al. 2006). Of interest, Raue et al. (2007) observed that older women who are experiencing a large degree of sarcopenia express the MuRF-1 gene at higher levels compared to young adults, but this is reversed with resistance exercise (Raue et al. 2007). Although there was no differ- ence in Atrogin-1 expression between the old and young subjects, after resistance exercise there was a pronounced upregulation of this gene in older women (Raue et al. 2007). 3.2 Anabolic Resistance Anabolic stimulators, such as insulin, insulin-like growth factors (IGF1), amino acids (AA) and muscle contraction, rapidly and significantly increase skeletal muscle protein synthesis in young healthy tissue. Increased rates of protein synthe- sis are a key feature of hypertrophy driving muscle growth. The effect of essential amino acids on the dose-dependent stimulation of muscle protein synthesis is even observed when circulating insulin concentrations were clamped (10 mIU/mL) (Cuthbertson et al. 2005) or when somatostatin was used to inhibit insulin and insulin-like growth factors in human subjects (Greenhaff et al. 2008). The aging- induced “resistance” to amino acids to the stimulation of muscle protein synthesis has previously been observed in humans and rodents (Guillet et al. 2004; Cuthbertson et al. 2005; Rasmussen et al. 2006; Prod’homme et al. 2005). Rennie and colleagues (Cuthbertson et al. 2005) termed the age-related inability of nutri- ents to induce an appropriate anabolic response as “anabolic resistance”. Cuthbertson et al. (2005) observed in older humans, following introduction of essential amino acids (EAA), there was a reduced increase in skeletal muscle protein synthesis that 339Exercise as a Countermeasure for Sarcopenia was correlated with increased concentrations of circulating and intramuscular EAA (leucine) compared to their young counterparts (Cuthbertson et al. 2005). The authors hypothesized that this was related to “anabolic resistance” that is distinguishable in aging muscle (Cuthbertson et al. 2005). Aging is associated with an inability of insulin to stimulate muscle protein synthesis and amino acid uptake in otherwise healthy, glucose-tolerant persons (Rasmussen et al. 2006; Guillet et al. 2004; Bell et al. 2006; Fujita et al. 2009). The decline in muscle protein anabolic response to insulin is likely to be responsible for the observed reduction in postprandial muscle protein anabolism in older people. Rasmussen et al. (2006) observed that protein synthesis does not increase in response to hyperinsulinemia in older adults, in contrast to young subjects (Rasmussen et al. 2006). Prod’homme (2005) reported that insulin and EAA had differential effects on muscle protein synthesis in aging animals (Prod’homme et al. 2005). These researchers observed that young and old animals had a similar response to insulin, while anabolic stimulation by EAA was completely abolished in the older animals. Insulin resistance of muscle protein metabolism with ageing may induce a slow but progressive decline in muscle protein content thereby con- tributing to the development of sarcopenia in older. It is well established that within a few hours of muscle contraction there is an increase in protein synthesis even in the fasted state. The contraction-induced effects on muscle protein synthesis have been previously shown to be decreased in older compared to young humans (Kumar et al. 2009; Sheffield-Moore et al. 2004). Welle et al. (1995) even observed this effect after a 3 week strength exercise pro- gram in male and female human subjects (Welle et al. 1995). We (Funai et al. 2006; Parkington et al. 2004) and others (Thomson and Gordon 2005, 2006; Thomson et al. 2009) have also observed an inhibition of an anabolic signaling in response to muscle contraction and/or overload in aging skeletal muscle. Funai et al. (2006) reported that anabolic signaling was increased in skeletal muscle after a single bout of in situ muscle contractile activity induced by high-frequency electrical stimula- tion (HFES) in adult animals, but these responses were attenuated in aged animals (Funai et al. 2006). However, the anabolic resistance attributed to aging muscle has not been observed in all studies (Reynolds et al. 2004; Paddon-Jones et al. 2004; Volpi et al. 2003; Drummond et al. 2009a; Short et al. 2003, 2004). Therefore, more study is needed to elucidate the significance of anabolic resistance to sarcopenia. 3.3 Anabolic Signaling The mammalian target of rapamycin (mTOR) signaling kinase, which can be acti- vated by Akt/Protein Kinase B (PKB), has emerged as a necessary effector of skeletal muscle growth in response to contraction and anabolic agents (for review see: Wang and Proud 2006; Bodine et al. 2001; Rommel et al. 2001). Insulin, amino acids and acute contractile activity have all been observed to increase the phospho- rylation of mTOR and its downstream targets, p70 ribosomal protein S6 kinase 1 340 D.A. Rivas and R.A. Fielding (S6K1) and 4E binding protein 1 (4EBP1). mTOR is a highly conserved, serine/ threonine kinase of the phosphatidylinositol kinase-related kinase family and is a key regulatory protein for a multiplicity of cell processes including, but not limited to, cell growth and differentiation, protein synthesis, and actin cytoskeletal organi- zation. The primary phosphorylation targets of mTOR are the threonine (Thr)389 site of S6K1 and the Thr37/46 sites of 4EBP1 that mediate translational initiation. The observation of decreased protein synthesis in response to anabolic stimula- tion with aging is believed to occur as a result of the inhibition of mTOR signaling (Wang and Proud 2006). Multiple studies that have utilized rapamycin, a highly potent inhibitor of mTOR activation, have observed decreased protein synthesis in vivo and in vitro (Drummond et al. 2009; Kubica et al. 2005, 2008; Fluckey et al. 2004; Kimball et al. 2000; Anthony et al. 2000; Grzelkowska et al. 1999). The inhibitory effect of rapamycin on mTOR activation and protein synthesis can even occur despite an effective anabolic stimulation (Vary et al. 2007; Rivas et al. 2009; Kubica et al. 2005; Anthony et al. 2000). Cuthbertson et al. (2005) hypothesized that the “anabolic resistance” that was observed in their older subjects was related to the reduced phosphorylation of mTOR and its downstream substrate S6K1 (Cuthbertson et al. 2005). We and others have observed an age induced attenuation of the Akt/ mTOR signaling pathway in response to contractile stimulation and overload (Funai et al. 2006; Hwee and Bodine 2009; Thomson and Gordon 2006; Parkington et al. 2004). Recently, Drummond et al. (2009) demonstrated that the contraction-induced increase of mTOR signaling, protein synthesis and extracellular related kinase sig- naling (ERK1/2) are reduced with prior rapamycin treatment in humans (Drummond et al. 2009b). These results provide some understanding for the role of mTOR in the initiation of protein synthesis in response to anabolic stimuli, such as muscle con- traction. However, there is some disagreement whether the phosphorylation of mTOR is responsible for the changes in the protein synthetic rates in response to an anabolic stimulation (Greenhaff et al. 2008). Greenhaff et al. (2008) recently demonstrated that changes in signaling protein phosphorylation can be almost completely be disconnected from protein synthesis with an anabolic stimulus such as insulin. 3.4 Skeletal Muscle Attenuation It is well understood that with advancing age there is a change in the composition of skeletal muscle. Lean muscle mass normally contributes up to 50% of total body weight in young adults but declines with age to 25% at 75–80 years (Koopman and van Loon 2009; Short et al. 2004). The loss in lean muscle mass is usually offset by gains in fat mass. Longitudinal studies have shown that fat mass increases with age peaking at about 60–75 years (Rissanen et al. 1988; Droyvold et al. 2006). Aging is associated with the increased accumulation of intramuscular fat as well as with an increase in the incidence of metabolic disorders such as insulin resistance (Tucker and Turcotte 2003; Nakagawa et al. 2007). Impaired lipid 341Exercise as a Countermeasure for Sarcopenia metabolism and increased visceral adiposity associated with aging are thought to contribute to the muscle atrophy associated with sarcopenia (Nakagawa et al. 2007). Researchers have observed the defects in lipid metabolism, such as increased intramuscular and circulating lipids, even in lean and otherwise healthy elderly persons (Nakagawa et al. 2007). Furthermore, studies have found signifi- cant difference in protein metabolism between obese and non-obese humans (Guillet et al. 2009; Nair et al. 1983; Jensen and Haymond 1991; Luzi et al. 1996). Goodpaster et al. (2000) observed that increased mid-thigh muscle attenuation (a marker of intramuscular lipids with CT scan) was related to the loss of muscular specific strength in 2,627 older men and women (Goodpaster et al. 2000). The concomitant age-related changes in body composition, obesity, impaired metabo- lism and low muscle mass have lead to the hypothesis that there may be a causal link between obesity and low strength. Growth factors (i.e. insulin and IGF1), AA and muscle contraction are known modulators of muscle protein synthesis and inhibitors of protein degradation and their capacity to stimulate muscle protein synthesis is impaired in both aging and obesity (Rasmussen et al. 2006; Guillet et al. 2009). Insulin resistance is also highly coupled with obesity and aging and results in decreased insulin-stimulated glucose uptake, protein synthesis and the inability to inhibit lipid uptake (Corcoran et al. 2007; Tucker and Turcotte 2003; Hawley and Lessard 2008; Rasmussen et al. 2006; Anderson et al. 2008; Guillet et al. 2009). Guillet et al. (2009) recently observed that obese humans had a decreased fractional synthetic rate during an amino acid infusion and insulin clamp in the basal and insulin-stimulated state compared to their age matched controls (Guillet et al. 2009). In addition to the evidence showing that high-fat feeding and obesity inhibit protein synthesis in response to an anabolic stimulus, there is also evidence of altered mTOR signaling in the basal and insulin- stimulated state (Guillet et al. 2004, 2009; Rivas et al. 2009; Anderson et al. 2008; Khamzina et al. 2005; Katta et al. 2009). For example, Katta et al. (2009) demon- strated in obese Zucker rats that mTOR signaling was inhibited in response to in situ HFES muscle contraction compared to their lean litter mates (Katta et al. 2009). However, studies report there is no relationship between acutely increased circulating free fatty-acids (artificially-induced with heparin treatment) and decreased protein synthesis (Katsanos et al. 2009) or impaired mTOR signaling (Lang 2006) in skeletal muscle. Although there is some contention regarding role of increased circulating free-fatty acids and reduced protein synthesis, the increased storage of fat in muscle during aging has been clearly demonstrated to have role in reduced muscle mass and functional impairment. 3.5 Skeletal Muscle Regeneration Aging skeletal muscle displays a significant reduction in regenerative capacity this leads to the inability to adapt to an increased load and is therefore less responsive to injury. The regenerative capacity of muscle fibers depends on a 342 D.A. Rivas and R.A. Fielding pool of myogenically specified undifferentiated mononuclear precursor stem cells called ‘satellite’ cells that appear to function as “reserve” myoblasts (for review see: Wagers and Conboy (2005), Gopinath and Rando (2008). Satellite cells (SC) are the primary stem cells in adult skeletal muscle, and are respon- sible for postnatal muscle growth, hypertrophy, regeneration and repair. SC were identified ultrastructurally and were named for their peripheral location beneath the basal lamina of the myofiber (Mauro 1961). SC are primarily in a quiescent, non-differentiating state, dividing infrequently under normal condi- tions in the adult but activated (reenter the cell cycle) by regenerative cues such as injury or exercise. Once activated, the cells will proliferate, increase in num- ber and the daughter cells (myoblasts) will repair damaged skeletal muscle by fusing to existing myofibers or generating new myofibers by fusing together (Hawke 2005). It is believed that muscle hypertrophy requires the addition of nuclei to existing myofibers (Adams 2006). This follows the premise that increases in fiber size must be associated with a proportional increase in myonuclei for the control of mRNA and protein production per volume of cytoplasm (Hawke 2005). Growth factors such as, interleukin (IL) 6, testosterone, IGF1 and the IGF isoform, mechanogrowth factor, have been identified as having a role in post-exercise hypertrophy (Vierck et al. 2000; Adams 2002; Sinha-Hikim et al. 2003). Of interest, Machida and Booth (2004) recently demonstrated a key role for the PI3K/Akt pathway in IGF induced SC proliferation (Machida and Booth 2004). The potential role of SC in age-induced muscle atrophy is not clear cut. Studies have either shown a similar (Dreyer et al. 2006a; Roth et al. 2000; Sinha-Hikim et al. 2006) or lower (Kadi et al. 2004; Renault et al. 2002) SC proportion in older adults when compared with young adults. It has been demonstrated that SC in aged muscle display a delayed response to activating stimuli and reduced proliferative expansion (Schultz and Lipton 1982; Conboy et al. 2003). Verdijk and colleagues have reported marked decreases in Type 2 versus Type 1 muscle fiber myonuclear domain size and a specific decrease in the Type 2 fiber satellite cell content in elderly humans (Verdijk et al. 2007). In a follow up study, these researchers observed that Type 2 muscle fiber atrophy and the associated lower satellite cell proportion in Type 2 versus Type 1 muscle fibers in older adults can be reversed by prolonged resistance type exercise training (Verdijk et al. 2009). Roth et al. (2001) have also reported that satellite cell proportion in young and older men and women was significantly increased as a result of 9 weeks of strength training (Roth et al. 2001b). Interestingly, older women demonstrated a significantly greater increase in SC content and the largest increase in the number of active satellite cells in response to strength training. Therefore, because of the significant role of SC in skeletal muscle regeneration, repair and hypertrophy unraveling their role in sarcopenia remains a high priority. Some possible mechanisms that contribute to sarcopenia are outlined in Fig. 1. Sarcopenia is a multifactorial process and the mechanisms that underlie it are only beginning to be elucidated. More research is needed determine their roles in the onset of sarcopenia. 343Exercise as a Countermeasure for Sarcopenia 4 Exercise as an Intervention for the Modulation of Sarcopenia As discussed earlier in this chapter, life-long habitual physical activity is the most effective preventative treatment for age-induced sarcopenia. Multiple groups have studied the effects of exercise training on energy metabolism and as a treatment for metabolic disorders such as, insulin resistance, obesity and type 2 diabetes (Hawley and Lessard 2008; Berger and Berchtold 1979; Wallberg-Henriksson and Holloszy 1984, 1985; Zierath 2002; Goodyear and Kahn 1998; Kelley and Goodpaster 2001; Musi and Goodyear 2006). Exercise training, with respect to substrate metabolism, is associated with enhanced oxidative capacity and insulin sensitivity, decreased intramuscular lipid storage and improved body composition (Hawley and Lessard 2008; Toledo et al. 2007; Richter and Ruderman 2009; Tanaka and Seals 2003; Lessard et al. 2007). There is growing evidence demonstrating the benefits of exercise late in life as a countermeasure for sarcopenia and its related functional limitations (Keysor 2003; Henwood and Taaffe 2005; Galvao and Taaffe 2005; Galvao et al. 2005). Regular physical activity is associated with greater functional capacity, increased appendicular muscle mass and reduced incidence of metabolic diseases and this is particularly observed in middle-aged and older adults (Sugawara et al. 2002; Harber et al. 2009b). Since the 1980s, numerous intervention studies have reported the benefits of resistance, aerobic and a combination (aerobic and resistance) of these exercise modalities for the treatment muscle loss and disability as a result of aging (Frontera et al. 1988; Tanaka and Seals 2003). The purpose of this section is to review the molecular events and whole-body benefits of the different modes of exercise for the treatment of sarcopenia. Fig. 1 A few possible mechanistic contributors to sarcopenia and its consequences 344 D.A. Rivas and R.A. Fielding 4.1 Aerobic Exercise Aerobic exercise is a widely recommended therapeutic agent for older adults because of its beneficial effects on cardiovascular and metabolic health, body com- position and improved function. Endurance exercise is based on movements per- formed with a high number of repetitions and low resistance. Maximal aerobic capacity (VO 2 max) is generally thought to be the best indicator of the capacity to perform aerobic exercise. Maximal oxygen consumption declines about 1% per year after the age of 25 in sedentary individuals. This is important since low aerobic capacity has been highly correlated with increased rates of all-cause mortality in numerous epidemiological studies (Paffenbarger et al. 1993, 1970; Leon et al. 1987; Morris et al. 1953a, b). However, in master athletes who participate in regular aerobic activity the decline in VO 2 max is only 0.5% per year (Tanaka and Seals 2003, 2008; Paffenbarger et al. 1993). It is thought that the key contributors to a decline in maximal aerobic capacity in sedentary individuals are a decrease in maximal cardiac output (Ogawa et al. 1992; Proctor et al. 1998), a decrease in muscle oxidative capacity (Ljubicic et al. 2009; Short et al. 2003; Conley et al. 2000a, b; Harber et al. 2009) and a decrease in metabolically active muscle mass with a concomitant increase in metabolically inactive fat mass (Paffenbarger et al. 1970; Goodpaster et al. 2000, 2006; Short et al. 2003; Proctor and Joyner 1997; Fleg and Lakatta 1988). When measuring VO 2 max normalized to muscle mass (as indexed by 24 h urinary creatinine excretion) in old and young men and women, Fleg and Lakkata (1988) reported that the age- induced decrease in VO 2 max is explained by the selective loss of muscle mass that accompanies aging. Recently, Proctor and Joyner (1997), when examining the effect of reduced muscle mass (and increased fat mass) on VO 2 max in the elderly, expressed maximal oxygen consumption relative to appendicular muscle mass (Proctor and Joyner 1997). They observed that 50% of the decline in VO 2 max, as a result of aging, was attributed to the age-induced decreases in muscle mass and increases in fat mass. Therefore, understanding the possible benefits from aerobic exercise for increasing maximal oxidative capacity and/or muscle mass in older adults could have implications for healthy aging. 4.1.1 Improving Oxidative Capacity Aerobic exercise of sufficient intensity and duration can significantly increase VO 2 max in middle aged and older adults (Huang et al. 2005; Malbut et al. 2002; Lanza et al. 2008). It has been hypothesized that increases in mitochondrial number, increases in the expression of mitochondrial proteins and/or an increase in the expression of transcription factors involved in mitochondrial biogenesis are mecha- nisms for the enhancement in post-exercise VO 2 max. Lanza et al. (2008) observed increases in mitochondrial ATP production rate (MAPR), citrate synthase (CS) activity, pparg-coactivator 1 a (PGC1a), mtDNA abundance. Of interest, the 345Exercise as a Countermeasure for Sarcopenia researchers also reported an increase in sirtuin 3 (SIRT3), a protein deacetylase that has been associated with the life prolonging benefits of caloric restriction, in aero- bically trained older individuals compared to their sedentary peers (Lanza et al. 2008). There is some evidence of a reduction in the activation of the energy sensor, AMP-activated protein kinase (AMPK), in response to endurance exercise in aging muscle (Reznick et al. 2007). However, Ljubicic and Hood (2009) observed no dif- ference with endurance-like contraction induced AMPK activation in high-oxida- tive red muscle between old and young animals (Ljubicic and Hood 2009). The researchers did observe an inhibition of AMPK activity in the less oxidative white muscle in the acute response to endurance-like contraction. This may be an impor- tant consequence because of AMPK has recently been observed to have a critical role in the regulation of muscle hypertrophy as a result of muscle overload (McGee et al. 2008; Thomson et al. 2009). 4.1.2 Increased Muscle Mass There has been minimal study on aerobic exercise and its effects on improving muscle function, increasing muscle mass and protein synthesis in the elderly. Some researchers have provided evidence that aerobic exercise was as proficient as resis- tance training at improving functional limitations associated with aging (Wood et al. 2001; Davidson et al. 2009; Coggan et al. 1992; Verney et al. 2006). For example, Davidson et al. (2009) reported that 6 months of resistance and aerobic exercise was associated with similar improvements in functional limitation in 136 previously sedentary, obese older men and women (Davidson et al. 2009). Researchers have previously reported that aerobic exercise does not alter muscle size in older individuals (Ferrara et al. 2006; Verney et al. 2006; Short et al. 2004; Weiss et al. 2007). However, Harber et al. (2009) have recently shown that a 12 week aerobic training intervention induced a 16.5% increase in single fiber cross sectional area (CSA) and a 20% increase in quadriceps muscle volume that was accompanied by improvements in whole muscle power and force production in healthy older women (Harber et al. 2009). The investigators hypothesized that their results differed from previous studies because their subjects were in good health and the body weights of their subjects were maintained throughout the intervention. Also, habitually endurance-trained elderly males have higher appendicular muscle mass, relative to body mass, compared to their sedentary controls (Sugawara et al. 2002). The increased muscle hypertrophy and appendicular muscle mass observed in these studies could be as a result of increases in protein synthesis observed after aerobic exercise (Harber et al. 2009a, b; Short et al. 2004; Fujita et al. 2007). Short et al. (2004) reported that men and women have a decline in whole-body protein metabolism as a result of aging. A 4 month aerobic exercise program had no effect on whole-body protein turnover but, significantly increased mixed muscle protein synthesis in the older subjects (Short et al. 2004). Fujita et al. (2007) have further shown an increase in insulin-stimulated muscle protein turnover as a result of an acute . between obesity and low strength. Growth factors (i.e. insulin and IGF1), AA and muscle contraction are known modulators of muscle protein synthesis and inhibitors of protein degradation and their. greater frequency and/ or longer duration (see Table 1). 3 Mechanisms of Muscle Atrophy Associated with Sarcopenia 3.1 Protein Synthesis and Degradation The maintenance of muscle mass is regulated. review see: Wagers and Conboy (2005), Gopinath and Rando (2008). Satellite cells (SC) are the primary stem cells in adult skeletal muscle, and are respon- sible for postnatal muscle growth, hypertrophy,