Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia

Abstract

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.

Inflammation, Aging and Cancer: Friend or Foe?

“…Severe acute inflammatory diseases (e.g., sepsis, respiratory diseases, meningitis, major trauma, etc), and perhaps anti-cancer drug-induced cachexia, anorexia and sarcopenia, often lead to multiple organ failure (MOF) (Coss et al, 2011, Hall et al, 2011, Harrois et al, 2009, Hotamisisligil 2006a, b, Lyman 2011, Okamoto 2002, Suzuki et al, 2011, Terrabui et al, 2007. In severe acute inflammatory conditions, potent pathogens and their products (e.g., endotoxins, pneumonia, meningitis, etc) can induce rapid destruction of vascular integrity allowing pathogens to gain direct access to host tissues at multiple sites and inducing expression of massive quantities of apoptotic factors and toxins ('cytokine storm' or 'immune tsunami') such as TNF-, ILs, strong oxidants (e.g., peroxynitriles) that can rapidly shift the balance between apoptosis and wound healing pathways in favor of growth-arresting properties of immune cells and causing severe damage to important host cellular components (e.g., mitochondrial oxidative damage, interruption in electron transfer system, changes in oxido-redux ratios, accumulation of free radicals and severe toxicity to intracellular and/or cytoplasmic membrane components) leading to increased risk of organ failure in lung, kidney, brain, central nervous system and/or heart, in a matter of hours or days (Akamizu et al, 2010, Aubert and Lansdorp 2008, Braun and Marks 2010a, b, Suzuki et al, 2011, Terrabui et al, 2007.…”

“…These drugs could induce simultaneous production of oxidants (e.g., superoxide-O2 -, nitric oxide-NO and peroxynitrite) that would disrupt and damage electron chain transport and detoxifying enzymes (e.g., cytochrome C electron carriers, glutathione-GSSG/GSH, NAD + /NADH and/or vitamin E regeneration pathways) and impair mechanisms of removal of reactive oxygen species (ROS), reactive nitrogen species (RNS), peroxides and byproducts of the citric acid cycle. Furthermore, drug-induced oxidative damage to mitochondrial integrity and function could further impact catabolism of muscle proteins that would induce sarcopenia, and oxidation of adipose tissues, leading to excessive loss of appetite and weight and MOF (Akamizu and Kangawa 2010, Alberts et al, 2011, Blum et al, 2011, Chen et al, 2011, Del Fabbro et al, 2011, Hall et al, 2011a, b, Okamoto 2002, Suzuki et al, 2011, Terrabui et al, 2007. Fig.…”

“…Several recent studies demonstrated increased risks of metastasis (cancer relapse) and additional immune suppression after radiotherapy and 'targeted' therapies in site-specific cancers (e.g., hepatic carcinoma, colon, lung, prostate, lymphoid tissues, etc). The life-threatening side effects of such 'targeted' therapies include development of cachexia, aneroxia, arterial hypertension, secondary interstitial pneumonia and diffuse alveolar damage and pulmonary edema, broncopneumonia, lung hemorrhage, pulmonary and venus thromboembolism, metastasis and cancer relapse, as well as depression and fatigue ('sickness behaviors') (Blum et al, 2011, Braun and Marks 2010, Del Fabbro et al, 2011, Elamin 2011, Hall et al, 2011a, b, Lukaszewicz and Payen 2010, Lyman 2011, Ranmsdale et al, 2011, Suzuki et al, 2011, Terrabui et al, 2007. In addition, 'targeted' therapy-induced cancer cachexia and associated involuntary excessive loss of weight and appetite in patients are accompanied by significant declines in nutritional intake (e.g., zinc, vitamin B, anti-oxidants, etc) that contribute to the metabolic abnormalities and conditions such as hypothyroidism,, hypoadrenalism, and hypogonadism as well as induction of systemic inflammation and excessive expression of inflammatory mediators (e.g., IL-6, IL-1 , IL-8 and TNF-, potent oxidants, etc).…”

Aging, sarcopenia and store-operated calcium entry

“…These complex modifications might help explain the puzzling fact that atrophy alone can only explain a part of the totality of power loss in aged muscles 8,9 as well as open the doors of our scientific inquiry to new signaling pathways that might contribute to the complex phenotype of the aged muscle. [8][9][10][11][12][13] But this is not the entire tale of SOCE in aging muscles. Recent studies in our lab suggest that SOCE and extracellular calcium entry might also play roles in modulating muscle myogenic differentiation as well as muscle adaptation to stress, such as heat shock.…”

Sarcopenia: literature review and results of own research

“…В ряде исследований подтверждена роль возрастзависимого увеличения оксидативно-го стресса в развитии нейромышечной дегене-рации и прогрессировании саркопении [11,14].…”