In healthy individuals, mitochondrial protein content of PGC-1α, citrate synthase, and mitochondrial creatine kinase are directly correlated with mitochondrial fusion, and fusion and are associated with increased exercise capacity (Garnier et al., 2005). Exercise training can successfully attenuate the cachectic condition when started prior to the onset of cachexia, even in the presence of high circulating cytokines (Puppa et al., 2011a). One possible mechanism for the protective effects of exercise is the increase in mitochondrial capacity. Exercise training has a large impact on mitochondrial capacity in skeletal muscle. One of the main changes in skeletal muscle with exercise training is the increase in mitochondrial capacity and content (Holloszy and Coyle, 1984). Repeated bouts of exercise show progressive and sustained increases in several mitochondrial proteins such as PGC-1α, mitochondrial transcription factor A (Tfam), and nuclear respiratory factors (NRF) (Baar et al., 2002; Gordon et al., 2001; Hood et al., 2006) which allow for mitochondrial biogenesis and increased mitochondrial function. As well as increasing mitochondrial biogenesis exercise training can increase expression of mitochondrial fusion proteins and decrease mitochondrial fission proteins (White et al., 2012c). Such changes may increase mTOR and reduce the chronic activation of AMPK and FOXO seen in cachexia thus suppressing protein degradation and inducing synthesis.
It is widely accepted that cancer cachexia affects glycolytic muscle prior to affecting the more oxidative muscles. By increasing the mitochondrial capacity of
skeletal muscle, making it more oxidative, the muscle may be protected. Exercise may be one potential therapeutic approach to combat this issue. The affects of exercise after the onset of cachexia and muscle loss are unknown. Exercise induces expression of fission related proteins immediately post; however, there is up regulation of mitochondrial fusion proteins and biogenesis after exercise. Although the cachectic muscle already has
increases in fission and decreased mitochondrial content, exercise may be able to reverse this condition and return the muscle to a state in which fully functional mitochondria are present. Several studies have shown that SS mitochondrial are more susceptible to change than the IMF mitochondria (Menshikova et al., 2006). Research still needs to be done to determine if the loss of mitochondria in cancer cachexia is specific to the SS population or if it extends to the IMF population. It is reasonable to assume that IMF mitochondria are decreased with severe cachexia considering the fact that the SS population only accounts for approximately 20% of muscle mitochondria and a decrease in IMF mitochondria would correlate with the decrease in muscle mass and force production. Once the muscle mass has been lost and the muscle is in a catabolic state it may not be able to be returned to the pre catabolic state, however exercise may be able to prevent further loss of muscle mass. More research needs to be done to examine the effects of exercise on muscle after the initiation of cachexia and if exercise after onset of cachexia is able to restore normal mitochondrial dynamics and function. Research investigating the effects of resistance exercise on cachectic patients’ ability to hypertrophy muscle is lacking and is an area for further investigation.
Few studies have looked at the effect of an acute bout of exercise on the regulation of mitochondrial fission and fusion. What research has been conducted demonstrates that mitochondria fission is increased after an acute bout of exercise while mitochondrial fusion is suppressed (Bo et al.; Cartoni et al., 2005; Ding et al.). Although there is little research available about the changes in mitochondrial dynamics with an acute bout of exercise, a wide body of literature shows that exercise, even an acute bout, up-regulates mitochondrial biogenesis, partially through the activation of AMPK. After an acute bout of exercise PGC-1α is rapidly up-regulated leading to a subsequent increase in mitochondrial associated gene transcription and mitochondrial biogenesis (Baar et al., 2002; Pilegaard et al., 2003). Up-regulation of these genes persists for up to 4 hours before returning to baseline levels (Pilegaard et al., 2000). Since the effects are short lived it shows the importance of regular physical activity to increase mitochondrial capacity. As well as increases in mitochondrial capacity, insulin sensitivity is increased immediately following an acute bout of exercise, in part due to the up-regulation of genes regulating glycolysis and fatty acid oxidation and overall improvements of metabolic flexibility.
Exercise is well known to help improve insulin sensitivity, and is commonly used to treat insulin resistance in various disease states including diabetes (Hawley, 2004), cachexia, and obesity (Bradley et al., 2008; Duncan et al., 2003). In healthy rodents, exercise improves both glucose tolerance (James et al., 1983) and insulin sensitivity (James et al., 1984). The exact mechanism is still unclear, however potential mechanisms by which exercise can improve insulin resistance are to reduce inflammation (Kondo et al., 2006; Mattusch et al., 2000), improve muscle respiratory capacity (Holloszy, 1967;
Mole et al., 1971; Oscai and Holloszy, 1971) and improve insulin signaling (Houmard et al., 1999). Both acute bouts of exercise and exercise training can have positive effects on insulin sensitivity. After an acute bout of exercise insulin sensitivity is increased for at least 16 hours and the effects can last up to 48 hours. These improvements in insulin sensitivity most likely stem from increases in skeletal muscle glucose transporter type 4, GLUT4, protein content and increased translocation of GLUT 4 to the plasma membrane. GLUT4 is a glucose transporter protein that is spread throughout the cytoplasm in the rested state. After ingestion of glucose or after exercise, GLUT4 moves from the cytosol and associates with the plasma membrane to take up glucose into the cell to be used as energy. GLUT4 can be stimulated both by insulin and by contraction. In the insulin resistant individual GLUT4 expression is not decreased in the skeletal muscle, but insulin stimulated signaling is suppressed (Handberg et al., 1990; Kahn, 1992) . The acute effects of exercise on glucose uptake occur in an insulin independent manner and rely mainly on the contraction stimulated increase in GLUT4 translocation (Brozinick et al., 1992; King et al., 1993). As mentioned previously these effects are short lived and if another bout of exercise or muscle contraction is not conducted the cells will return to the pre exercise state.
Improvements in lipid metabolism are important for the maintenance of insulin sensitivity. When there is an accumulation of lipid in the body it can inhibit insulin signal transduction. Exercise up regulates lipid oxidation and improves mitochondrial capacity to perform beta oxidation. While mitochondrial capacity is decreased in cancer cachexia (White et al., 2011a) exercise training is able to up regulate mitochondrial capacity even in conditions when cancer and inflammation are present (Puppa et al., 2011a). Skeletal
muscle mitochondrial function plays a pivotal role in muscle glucose uptake, and
impairments in the oxidative capacity have been associated with insulin resistance (Lanza and Nair, 2009; Morino et al., 2006). Altered mitochondria content is also related to a diminished ability of muscle to efficiently oxidize fatty acids, leading to decreased
muscle metabolic flexibility (Chomentowski et al.). The loss of muscle oxidative capacity in cancer cachexia corresponds with severe insulin resistance as seen by the inability to clear glucose during a glucose tolerance test late in cachexia (Puppa et al., 2011c). Training maintains the increased levels of mitochondria and improves metabolic flexibility. As metabolic flexibility is improved, insulin sensitivity is also improved.
Exercise training can result in long term improvements on insulin sensitivity. Insulin acts through the PI3K signaling pathway to up regulate protein synthesis and muscle glucose uptake. PI3K has been shown to be decreased in insulin resistant individuals (Goodyear et al., 1995) and is one reason for the decrease in insulin stimulated translocation of GLUT4 with insulin resistance. Exercise increases PI3K signaling potentially through increases in the insulin receptor substrate; however the evidence is variable as reviewed by Hawley et al (Hawley and Lessard, 2008). PI3K activates downstream signaling to enhance glucose uptake and improve insulin sensitivity. As well as increasing the ability of insulin to activate its signaling cascade directly exercise training causes an increase in the activation of AMPK. As mentioned earlier AMPK is an energy sensor for the cell and can regulate lipid metabolism, protein synthesis, mitochondrial biogenesis and glucose uptake, which are all dysregulated in cancer. Exercise training increases protein levels of AMPK, but despite the increase in AMPK exercise training induced an increase in muscle protein synthesis even in the
cachectic condition. The increased muscle protein synthesis rates are due to activation of the IGF-1 Akt/mTOR pathway that is suppressed in cancer cachexia (White et al., 2011b). Exercise is also able to attenuate the chronic activation of AMPK that is seen with severe muscle wasting (Puppa et al., 2011a; White et al., 2011b). The improvements in the regulation of AMPK activity may be due to the improvements in glucose uptake which could alleviate the energy stress that is placed on the muscle due to the cancer and metabolic inflexibility.
Exercise and IL-6
Exercise benefits have been well documented in patients with many chronic diseases, and exercise is widely recommended for obese and insulin resistant patients. Exercise has the potential to challenge systemic disorders and local intracellular signaling that regulates muscle homeostasis. The potential beneficial effects of exercise are
dependent on many variables, including exercise type (i.e., endurance or resistance), and whether the muscle responses are induced by a single acute bout of exercise, or an adaptation occurring because of repeated exercise bouts. We have published that
treadmill exercise trained cachectic mice over-expressing IL-6 are not susceptible to body weight and muscle mass loss despite elevated muscle inflammatory signaling (Puppa et al., 2011d). IL-6 is known to be a key player in the adaptations to skeletal muscle
contraction. Skeletal muscle is known to be an endocrine organ that can secrete IL-6 after contraction and plays a role in muscle metabolism. IL-6KO mice have been used to study the necessity of IL-6 for exercise and load induced adaptations, and IL-6KO mice have been shown to have altered adaptations. IL-6KO mice that have undergone synergistic ablation have been shown to have decreased myonuclei number and decreased satellite
cell activation (Serrano et al., 2008) and have been shown to have an increase in extracellular matrix remodeling and non contractile tissue (White et al., 2009) after overload. It has also been reported that IL-6KO mice have a decreased endurance
capacity, an increased fat mass, and decreased oxygen consumption during exercise by 8 months of age (Faldt et al., 2004). Related to muscle protein and mitochondrial responses to exercise, Kelly et al. demonstrated that activation of AMPK is suppressed in IL-6KO mice and there was lower activation of AMPK after exercise compared with the wild type controls (Kelly et al., 2004). After a bout of exercise, high fat diet (HFD) fed IL-6KO mice showed decreased glucose uptake in the EDL and these mice with access to wheels still developed a decreased systemic insulin sensitivity (Benrick et al., 2012). Since AMPK is a key player in mitochondrial biogenesis and regulating protein synthesis these data suggest that there will be alterations in these parameters; however, this remains to be examined. While these studies have shown that a systemic IL-6 knockout has alterations in skeletal muscle adaptations some of which could be induced by the lack of IL-6 on other tissues such as the liver and adipose tissue where IL-6 is known to play a vital role, the direct role of IL-6 signaling on skeletal muscle remains to be examined in healthy or diseased models.