The first suggestion that physical exercise results in free radical-mediated damage to tissues appeared in 1978, and the past three decades have resulted in a large growth of knowledge regarding exercise and oxidative stress. Although the sources of oxidant production during exercise continue to be debated, it is now well established that both resting and contracting skeletal muscles produce reactive oxygen species and reactive nitrogen species. Importantly, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Furthermore, oxidants can modulate a number of cell signaling pathways and regulate the expression of multiple genes in eukaryotic cells. This oxidant-mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant-modulated genes have been identified and include antioxidant enzymes, stress proteins, DNA repair proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species promote contractile dysfunction resulting in muscle weakness and fatigue. Ongoing research continues to probe the mechanisms by which oxidants influence skeletal muscle contractile properties and to explore interventions capable of protecting muscle from oxidant-mediated dysfunction.

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Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production

Context Cognitive impairment and functional disability are major determinants of caregiving needs and societal health care costs. Although the incidence of severe sepsis is high and increasing, the magnitude of patients' long-term cognitive and functional limitations after sepsis is unknown. Objective To determine the change in cognitive impairment and physical functioning among patients who survive severe sepsis, controlling for their presepsis functioning. Design, Setting, and Patients A prospective cohort involving 1194 patients with 1520 hospitalizations for severe sepsis drawn from the Health and Retirement Study, a nationally representative survey of US residents (1998-2006). A total of 9223 respondents had a baseline cognitive and functional assessment and had linked Medicare claims; 516 survived severe sepsis and 4517 survived a nonsepsis hospitalization to at least 1 follow-up survey and are included in the analysis. Main Outcome Measures Personal interviews were conducted with respondents or proxies using validated surveys to assess the presence of cognitive impairment and to determine the number of activities of daily living (ADLs) and instrumental ADLs (IADLs) for which patients needed assistance. Results Survivors' mean age at hospitalization was 76.9 years. The prevalence of moderate to severe cognitive impairment increased 10.6 percentage points among patients who survived severe sepsis, an odds ratio (OR) of 3.34 (95% confidence interval [CI], 1.53-7.25) in multivariable regression. Likewise, a high rate of new functional limitations was seen following sepsis: in those with no limits before sepsis, a mean 1.57 new limitations (95% CI, 0.99-2.15); and for those with mild to moderate limitations before sepsis, a mean of 1.50 new limitations (95% CI, 0.87-2.12). In contrast, nonsepsis general hospitalizations were associated with no change in moderate to severe cognitive impairment (OR, 1.15; 95% CI, 0.80-1.67; P for difference vs sepsis = .01) and with the development of fewer new limitations (mean among those with no limits before hospitalization, 0.48; 95% CI, 0.39-0.57; P for difference vs sepsis Conclusions Severe sepsis in this older population was independently associated with substantial and persistent new cognitive impairment and functional disability among survivors. The magnitude of these new deficits was large, likely resulting in a pivotal downturn in patients' ability to live independently.

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Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe Sepsis

Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) is a complex disease involving more than airflow obstruction. Airflow obstruction has profound effects on cardiac function and gas exchange with systemic consequences. In addition, as COPD results from inflammation and/or alterations in repair mechanisms, the "spill-over" of inflammatory mediators into the circulation may result in important systemic manifestations of the disease, such as skeletal muscle wasting and cachexia. Systemic inflammation may also initiate or worsen comorbid diseases, such as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia, lung cancer, depression and diabetes. Comorbid diseases potentiate the morbidity of COPD, leading to increased hospitalisations, mortality and healthcare costs. Comorbidities complicate the management of COPD and need to be evaluated carefully. Current therapies for comorbid diseases, such as statins and peroxisome proliferator-activated receptor-agonists, may provide unexpected benefits for COPD patients. Treatment of COPD inflammation may concomitantly treat systemic inflammation and associated comorbidities. However, new broad-spectrum anti-inflammatory treatments, such as phosphodiesterase 4 inhibitors, have significant side-effects so it may be necessary to develop inhaled drugs in the future. Another approach is the reversal of corticosteroid resistance, for example with effective antioxidants. More research is needed on COPD comorbidities and their treatment.

https://erj.ersjournals.com/content/erj/33/5/1165.full.pdf

Systemic manifestations and comorbidities of COPD

ESPEN guideline on clinical nutrition in the intensive care unit

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Cellular and molecular mechanisms of muscle atrophy

Sepsis is a major cause of morbidity and mortality in critically ill patients, and despite advances in management, mortality remains high. In survivors, sepsis increases the risk for the development of persistent acquired weakness syndromes affecting both the respiratory muscles and the limb muscles. This acquired weakness results in prolonged duration of mechanical ventilation, difficulty weaning, functional impairment, exercise limitation, and poor health-related quality of life. Abundant evidence indicates that sepsis induces a myopathy characterized by reductions in muscle force-generating capacity, atrophy (loss of muscle mass), and altered bioenergetics. Sepsis elicits derangements at multiple subcellular sites involved in excitation contraction coupling, such as decreasing membrane excitability, injuring sarcolemmal membranes, altering calcium homeostasis due to effects on the sarcoplasmic reticulum, and disrupting contractile protein interactions. Muscle wasting occurs later and results from increased proteolytic degradation as well as decreased protein synthesis. In addition, sepsis produces marked abnormalities in muscle mitochondrial functional capacity and when severe, these alterations correlate with increased death. The mechanisms leading to sepsis-induced changes in skeletal muscle are linked to excessive localized elaboration of proinflammatory cytokines, marked increases in free-radical generation, and activation of proteolytic pathways that are upstream of the proteasome including caspase and calpain. Emerging data suggest that targeted inhibition of these pathways may alter the evolution and progression of sepsis-induced myopathy and potentially reduce the occurrence of sepsis-mediated acquired weakness syndromes.

/pdf/sepsis-induced-myopathy-1ss931o3f6.pdf

Sepsis-induced myopathy.

Introduction
Studies indicate that mechanically ventilated patients develop significant diaphragm muscle weakness, but the etiology of weakness and its clinical impact remain incompletely understood. We assessed diaphragm strength in mechanically ventilated medical ICU patients, correlated the development of diaphragm weakness with multiple clinical parameters, and examined the relationship between the level of diaphragm weakness and patient outcomes.

https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1010&context=internalmedicine_facpub

Diaphragm weakness in mechanically ventilated critically ill patients

Loss of functional capacity of skeletal muscle is a major cause of morbidity in patients with a number of acute and chronic clinical disorders, including sepsis, chronic obstructive pulmonary disease, heart failure, uremia, and cancer. Weakness in these patients can manifest as either severe limb muscle weakness (even to the point of virtual paralysis), respiratory muscle weakness requiring mechanical ventilatory support, and/or some combination of these phenomena. While factors such as nutritional deficiency and disuse may contribute to the development of muscle weakness in these conditions, systemic inflammation may be the major factor producing skeletal muscle dysfunction in these disorders. Importantly, studies conducted over the past 15 years indicate that free radical species (superoxide, hydroxyl radicals, nitric oxide, peroxynitrite, and the free radical-derived product hydrogen peroxide) play an key role in modulating inflammation and/or infection-induced alterations in skeletal muscle function. Substantial evidence exists indicating that several free radical species can directly alter contractile protein function, and evidence suggests that free radicals also have important effects on sarcoplasmic reticulum function, on mitochondrial function, and on sarcolemmal integrity. Free radicals also modulate activation of several proteolytic pathways, including proteosomally mediated protein degradation and, at least theoretically, may also influence pathways of protein synthesis. As a result, free radicals appear to play an important role in regulating a number of downstream processes that collectively act to impair muscle function and lead to reductions in muscle strength and mass in inflammatory conditions.

Free radical-mediated skeletal muscle dysfunction in inflammatory conditions.

Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunct...

https://www.physiology.org/doi/pdf/10.1152/ajpregu.90902.2008

Leigh Ann Callahan

Papers

Sepsis-induced myopathy.

Diaphragm weakness in mechanically ventilated critically ill patients

Free radical-mediated skeletal muscle dysfunction in inflammatory conditions.

MitoQ administration prevents endotoxin-induced cardiac dysfunction

Diaphragm Dysfunction in Critical Illness.