Date Published: August 7, 2011
Publisher: Impact Journals LLC
Author(s): Derek T. Hall, Jennifer F. Ma, Sergio Di Marco, Imed-Eddine Gallouzi.
Muscle atrophy—also known as muscle wasting—is a debilitating syndrome that slowly develops with age (sarcopenia) or rapidly appears at the late stages of deadly diseases such as cancer, AIDS, and sepsis (cachexia). Despite the prevalence and the drastic detrimental effects of these two syndromes, there are currently no widely used, effective treatment options for those suffering from muscle wasting. In an attempt to identify potential therapeutic targets, the molecular mechanisms of sarcopenia and cachexia have begun to be elucidated. Growing evidence suggests that inflammatory cytokines may play an important role in the pathology of both syndromes. As one of the key cytokines involved in both sarcopenic and cachectic muscle wasting, tumor necrosis factor α (TNFα) and its downstream effectors provide an enticing target for pharmacological intervention. However, to date, no drugs targeting the TNFα signaling pathway have been successful as a remedial option for the treatment of muscle wasting. Thus, there is a need to identify new effectors in this important pathway that might prove to be more efficacious targets. Inducible nitric oxide synthase (iNOS) has recently been shown to be an important mediator of TNFα-induced cachectic muscle loss, and studies suggest that it may also play a role in sarcopenia. In addition, investigations into the mechanism of iNOS-mediated muscle loss have begun to reveal potential therapeutic strategies. In this review, we will highlight the potential for targeting the iNOS/NO pathway in the treatment of muscle loss and discuss its functional relevance in sarcopenia and cachexia.
Muscle wasting is a serious affliction commonly found in aging individuals. It results from the combined effects of muscle atrophy as well as muscle cell death, leading to an overall loss of muscle mass and a decrease in muscle strength [1, 2]. The results of muscle wasting are often debilitating and are associated with an increased risk of mortality. In the elderly population, muscle wasting may be found in both acute (cachectic) and chronic (sarcopenic) forms. These two diseased states, though highly interconnected, represent two distinct conditions. Whereas cachexia is only found to develop in the presence of an overlying inflammatory condition, sarcopenia is an age-dependent geriatric syndrome that can develop in the absence of any other apparent pre-existing conditions (Figure 1) [1, 2]. Sarcopenia is associated with a gradual loss of muscle, in contrast to the rapid atrophy associated with cachexia . In some patients, cachexia may lead to the onset of sarcopenia, inducing a state known as cachexia-related sarcopenia [1, 3]. Furthermore, there may be differences in the underlying molecular mechanisms of the two disease states. For example, whereas the importance of ubiquitin-mediated degradation is well established in cachexia, there is conflicting evidence for its role in sarcopenia, suggesting that the proteasomal degradation pathway may play a lesser role in age-related muscle wasting . The existence of sarcopenia in the absence of a primary trigger, as well as the more gradual muscle atrophy that is not associated with an upregulation in ubiquitin-mediated degradation, distinguishes it from cachexia. However, the ability of cachexia to induce sarcopenia underscores the potentially overlapping molecular mechanisms of the two syndromes. Both result in similar changes in the overall metabolic state of muscle fibers, leading to atrophy, and the molecular mechanisms leading to this state may, in fact, share certain common pathways [1, 5]. Indeed, studies have implicated inflammatory cytokines as important humoral factors in the pathology of both sarcopenic and cachectic muscle wasting (Figure 2).
The term sarcopenia—a combination of the Greek words sarx, meaning “flesh”, and penia, meaing “loss”—was first coined by Dr. Rosenberg to describe the phenomenon whereby aging individuals would exhibit a gradual loss of muscle mass . Over the years, several clinical definitions of sarcopenia have been proposed [2, 3, 16]. The most recent one defines sarcopenia as the “age-associated loss of skeletal muscle mass and function” . This loss of muscle is considered one of the most dramatic effects of aging on the quality of life of aged individuals . Sarcopenia is a highly prevalent syndrome affecting a large portion of the geriatric population. It is estimated that 25% of individuals over the age of 64 suffer from sarcopenia, and that percentage is doubled in individuals over the age of 80 [17, 18]. Starting at age 30, muscle mass begins to decline at an average rate of 1-2% per year . This gradual loss of muscle eventually leads to increased frailty, resulting in disability and a dramatic increase in the rate of mortality . Currently, the most effective way to prevent sarcopenic muscle loss is through strength training exercise combined with or without amino acid nutritional supplementation [21-23]. However, keeping to a regimented, intensive exercise program may be too difficult or undesirable for many elderly patients . Therefore, it is still important to develop drug-therapies for the treatment of sarcopenia. To date, pharmacological therapies for sarcopenia have been met with limited success [21, 23]. Thus, it is important to elucidate the molecular mechanism of sarcopenia in order to identify new therapeutic targets.
Cachexia is a fatal syndrome that develops in patients with chronic inflammatory conditions such as cancer, AIDS, and sepsis [48, 49]. Cachexia is characterized by a severe wasting (up to 75%) of skeletal muscle tissue . This dramatic loss of muscle mass leads to loss of motor function, an overall decrease in the quality of life, and a reduced survival rate (Figure 1) . It has been estimated that 2% of the general population is afflicted with early-stage cachexia (defined as weight loss in association with a chronic disease). Of these 2%, it is unknown how many progress to late stage cachexia . However, it is important to note, that cachexia mostly affects patients with chronic diseases. Within this subpopulation, the prevalence of early stage cachexia can reach as high as 36%, as is the case for chronic obstructive pulmonary disease (COPD) . It has been shown that up to 22% of all cancer-related deaths are directly caused by cachexia, rather than the primary malignancy . Death is frequently caused by extensive wasting of the respiratory muscles, leading to hypostatic pneumonia [53, 54]. Cachexia is often accompanied by loss of adipose tissue, anemia, and anorexia, all of which further contribute to its detrimental effects [48, 49]. Despite the importance of muscle wasting syndrome in the pathology of several prevalent diseases, very few treatment options exist for patients with cachexia.
As described above, two of the main mechanisms by which TNFα-induced NF-κB activation triggers muscle wasting are through an upregulation of the ubiquitin-proteasome pathway by the increased expression of MuRF1, as well as through an increase in the expression of iNOS, leading to oxidative stress [10, 11, 71, 72]. While, as described above, the TNFα-mediated activation of the proteasome has received a lot of attention in the recent years, specifically as a potential target for therapy against muscle wasting, the implication of the iNOS/NO pathway remained neglected despite several studies linking it to the TNFα-induced muscle atrophy [11, 12, 14]. iNOS converts L-arginine to citrulline, releasing NO in the process. Under certain conditions, NO reacts with superoxide anions (O2-) to form the toxic molecule peroxynitrite (ONOO-), leading to oxidative stress and muscle fiber loss (Figure 3) [12, 80]. Although the detailed mechanism of how NO-induced stress leads to muscle wasting remains to be elucidated, the production of NO, and the subsequent formation of peroxynitrite, has been shown to decrease mRNA levels of MyoD—an important transcription factor involved in myogenesis and maintenance of skeletal muscle [12, 73].
While mounting evidence supports the implication of the iNOS/NO pathway in muscle wasting, many questions remain unanswered. It is still unknown whether NO or a product of the iNOS/NO pathway compromises muscle integrity by affecting the expression of other key components, besides Jun-D and MyoD, involved in muscle fibers formation, maintenance or both. Moreover, the way by which peroxynitrite leads to the degradation of MyoD mRNA is still elusive. In addition, it is unclear whether peroxynitrite plays a role in NO-mediated inhibition of protein synthesis and Jun-D activity. Further investigation is required to more clearly establish the role of peroxynitrite in muscle wasting. Nevertheless, the ability of peroxynitrite scavengers and antioxidants to prevent muscle wasting symptoms suggests that targeting peroxynitrite may be an efficacious treatment option. Furthermore, given the role of iNOS/NO in other important physiological pathways, such as normal muscle repair and the innate immune response [111, 112], targeting peroxynitrite, either directly or by inhibition of ROS generation, may prove to be a more desirable treatment as it would allow for inhibition of NO-mediated atrophic effects, without affecting NO-mediated beneficial effects. In the end, sarcopenia and cachexia are multifactoral syndromes, and it is unlikely that any one treatment will provide a miracle cure. Instead, a combination of therapies targeting multiple effectors will likely be necessary. To this end, identifying other direct-effectors of muscle wasting as targets for the development of inhibition therapies is an important first step towards the search for a cure for muscle wasting syndrome.