Recent advances in the understanding of skeletal muscle fatigue

Prolonged or repeated contractions of skeletal muscles lead to impaired muscle function, fatigue develops. Fatigue may be caused by factors within the muscle cells (peripheral fatigue) and diminished activation from the central nervous system (central fatigue). The relative importance of peripheral central fatigue depends on the type of physical activity. Central fatigue may be more prominent in elderly subjects. Increased concentration of inorganic phosphate seems to be of major importance for acute peripheral fatigue. There is frequently a long-lasting depression of force production after fatiguing muscle activity, especially at low stimulation frequencies. This low-frequency fatigue seems to be due to "structural" changes in proteins involved in intracellular Ca handling. Contractions in which the muscle is stretched (eccentric contractions) cause muscle weakness and damage. The initial defect induced by eccentric contractions is overstretched sarcomeres, but these appear to cause localized membrane tears that subsequently contribute to muscle weakness and damage.     

Peripheral and Central Mechanisms of Fatigue in Inflammatory and Noninflammatory Rheumatic Diseases

Fatigue is a common symptom in a large number of medical and psychological disorders, including many rheumatologic illnesses. A frequent question for health care providers is related to whether reported fatigue is ??in the mind?? or ??in the body????that is, central or peripheral. If fatigue occurs at rest without any exertion, this suggests psychological or central origins. If patients relate their fatigue mostly to physical activities, including exercise, their symptoms can be considered peripheral. However, most syndromes of fatigue seem to depend on both peripheral and central mechanisms. Sometimes, muscle biopsy with histochemistry may be necessary for the appropriate tissue diagnosis, whereas serological tests generally provide little reliable information about the origin of muscle fatigue. Muscle function and peripheral fatigue can be quantified by contractile force and action potential measurements, whereas validated questionnaires are frequently used for assessment of mental fatigue. Fatigue is a hallmark of many rheumatologic conditions, including fibromyalgia, myalgic encephalitis/chronic fatigue syndrome, rheumatoid arthritis, systemic lupus, Sjogren??s syndrome, and ankylosing spondylitis. Whereas many studies have focused on disease activity as a correlate to these patients?? fatigue, it has become apparent that other factors, including negative affect and pain, are some of the most powerful predictors for fatigue. Conversely, sleep problems, including insomnia, seem to be less important for fatigue. There are several effective treatment strategies available for fatigued patients with rheumatologic disorders, including pharmacological and nonpharmacological therapies.     

Importance of fatigue and its measurement in chronic liver disease

The mechanisms of fatigue in the group of people with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are protean. The liver is central in the pathogenesis of fatigue because it uniquely regulates much of the storage, release and production of substrate for energy generation. It is exquisitely sensitive to the feedback controlling the uptake and release of these energy generation substrates. Metabolic contributors to fatigue, beginning with the uptake of substrate from the gut, the passage through the portal system to hepatic storage and release of energy to target organs (muscle and brain) are central to understanding fatigue in patients with chronic liver disease. Inflammation either causing or resulting from chronic liver disease contributes to fatigue, although inflammation has not been demonstrated to be causal. It is this unique combination of factors, the nexus of metabolic abnormality and the inflammatory burden of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis that creates pathways to different types of fatigue. Many use the terms central and peripheral fatigue. Central fatigue is characterized by a lack of self-motivation and can manifest both in physical and mental activities. Peripheral fatigue is classically manifested by neuromuscular dysfunction and muscle weakness. Therefore, the distinction is often seen as a difference between intention (central fatigue) versus ability (peripheral fatigue). New approaches to measuring fatigue include the use of objective measures as well as patient reported outcomes. These measures have improved the precision with which we are able to describe fatigue. The measures of fatigue severity and its impact on usual daily routines in this population have also been improved, and they are more generally accepted as reliable and sensitive. Several approaches to evaluating fatigue and developing endpoints for treatment have relied of biosignatures associated with fatigue. These have been used singly or in combination and include: physical performance measures, cognitive performance measures, mood/behavioral measures, brain imaging and serological measures. Treatment with non-pharmacological agents have been shown to be effective in symptom reduction, whereas pharmacological agents have not been shown effective.     

Muscle fatigue in women with primary biliary cirrhosis： Spectral analysis of surface electromyography

AIM: To evaluate the myoelectric manifestations of peripheral fatigability in patients with primary biliary cirrhosis in comparison to healthy subjects. METHODS: Sixteen women with primary biliary cirrhosis without comorbidity and 13 healthy women matched for age and body mass index (BMI) completed the self-reported questionnaire fatigue impact scale. All subjects underwent surface electromyography assessment of peripheral fatigability. Anterior tibial muscle isometric voluntary contraction was executed for 20 s at 80% of maximal voluntary isometric contraction. During the exercise electromyographic signal series were recorded and root mean square (expression of central drive) as well as mean and median of electromyographic signal frequency spectrum (estimates of muscle fatigability) were computed. Each subject executed the trial two times. EMG parameters were normalized, then linear regression was applied and slopes were calculated. RESULTS: Seven patients were fatigued (median fatigue impact scale score: 38, range: 26-66) and 9 were not fatigued (median fatigue impact scale score: 7, range: 0-17). The maximal voluntary isometric contraction was similar in patients (82, 54-115 N) and controls (87, 74-101 N), and in patients with high (81, 54-115 N) and low fatigue impact scale scores (86, 65-106 N). Root mean square as well as mean and median of frequency spectrum slopes were compared with the Mann-Whitney U test, and no significant difference was found between fatigued and non-fatigued patients and controls. CONCLUSION: No instrumental evidence of peripheral fatigability can be found in women with primary biliary cirrhosis but no comorbidity, suggesting that fatigue in such patients may be of central origin.     

Peripheral pain mechanisms in chronic widespread pain

Clinical symptoms of chronic widespread pain (CWP) conditions like fibromyalgia (FM), include pain, stiffness, subjective weakness, and muscle fatigue. Muscle pain in CWP is usually described as fluctuating and often associated with local or generalised tenderness (hyperalgesia and/or allodynia). This tenderness related to muscle pain depends on increased peripheral and/or central nervous system responsiveness to peripheral stimuli, which can be either noxious (hyperalgesia) or non-noxious (allodynia). For example, patients with muscle hyperalgesia will rate painful muscle stimuli higher than normal controls, whereas patients with allodynia may perceive light touch as painful, something that a 'normal' individual will never describe as painful. The pathogenesis of such peripheral and/or central nervous system changes in CWP is unclear, but peripheral soft tissue changes have been implicated. Indirect evidence from interventions that attenuate tonic peripheral nociceptive impulses in patients with CWP syndromes like FM suggest that overall FM pain is dependent on peripheral input. More importantly, allodynia and hyperalgesia can be improved or abolished by removal of peripheral impulse input. Another potential mechanism for CWP pain is central disinhibition. However, this pain mechanism also depends on tonic impulse input, even if only inadequately inhibited. Thus, a promising approach to understanding CWP is to determine whether abnormal activity of receptors in deep tissues is fundamental to the development and maintenance of this chronic pain disorder. CONCLUSIONS: Most CWP patients present with focal tissue abnormalities including myofascial trigger points, ligamentous trigger points or osteoarthritis of the joints and spine. While not predictive for the development of CWP, these changes nevertheless represent important pain generators that may initiate or perpetuate chronic pain. Local chemical mediators, including lactic acid, adenosine triphosphate (ATP) and cytokines, seem to play an important role in sensitising deep tissue nociceptors of CWP patients. Thus, the combination of peripheral impulse input and increased central pain sensitivity may be responsible for widespread chronic pain disorders including FM.     

Fatigue and fibromyalgia syndrome: clinical and neurophysiologic pattern

The concept of 'fatigue' is strictly related to parameters of the setting in which fatigue is measured. Therefore, it is mandatory to provide a definition of fatigue and the modalities of its use. This is of pivotal importance with regard to the fibromyalgia (FM) syndrome, where fatigue is the most invalidating symptom and where, paradoxically, no clear and widely accepted definition of fatigue is available in the literature as yet. In the clinical setting, fatigue can be measured by different methods of various complexity. The simplest technique to assess fatigue involves the use of a visual analogue scale (VAS); however, a number of scales with differing levels of complexity are available for use. It is, often, difficult to detach the term 'fatigue' from tiredness and task failure, which correspond to two completely distinguished forms of fatigue: one with central origin (tiredness) and another which is localised within the muscle (peripheral muscle fatigue). The former is related to changes in motor-unit-recruitment strategies, whereas the latter is attributed to changes in membrane properties. To extensively assess fatigue and, partially, to avoid confusion among the types of fatigue described above, a number of laboratory tests have been developed; among these, there are multichannel surface electromyography (EMG) recordings. Using this type of an approach, it is possible the estimation of motor unit location within the muscle, the decomposition of the surface EMG (sEMG) interference signal into constituent trains of motor unit action potentials (MUAPs) and the analysis of single unit properties.     

Understanding fatigue in primary biliary cholangitis: From pathophysiology to treatment perspectives

Fatigue is considered one of the most frequent and debilitating symptoms in primary biliary cholangitis (PBC), affecting over 50% of PBC patients. One in five patients with PBC suffer from severe fatigue, which significantly impairs quality of life. Fatigue is made up of a central and a peripheral component, whose pathophysiology is still greatly unresolved. Central fatigue is characterised by a lack of self-motivation and can manifest both in physical and mental activities (lack of intention). Peripheral fatigue includes neuromuscular dysfunction and muscle weakness (lack of ability). Peripheral fatigue could be explained by an excessive deviation from aerobic to anaerobic metabolism leading to excessive lactic acid accumulation and therefore accelerated decline in muscle function and prolonged recovery time. As opposed to itching, and with the exception of end-stage liver disease, fatigue is not related to disease progression. The objective of this review is to outline current understanding regarding the pathophysiology of fatigue, the role of comorbidities and contributing factors, the main tools for fatigue assessment, the failed therapeutic options, and future treatment perspectives for this disabling symptom. Since fatigue is an extremely common and debilitating symptom and there is still no licensed therapy for fatigue in PBC patients, further research is warranted to understand its causative mechanisms and to find an effective treatment.     

磁脉冲刺激技术在呼吸疾病中的应用

磁脉冲刺激技术是一种无痛、无创,能够有效地刺激呼吸性神经中枢、膈神经和躯干神经肌肉的新型手段,已经应用于呼吸科和急重症监护室,供医生判定患者呼吸中枢生理病理性改变,评定膈肌和身体功能状况以及进行呼吸肌康复训练评价.由于磁脉冲刺激技术在呼吸系统疾病的检测和治疗方面具有明显的优越性和实用性,因而有必要对其在呼吸疾病中的应用现状加以综合与评论.     

Exercise training in heart failure

The reduction of exercise capacity with early occurrence of fatigue and dyspnea is a hallmark of heart failure syndrome. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism, and function are present. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training in heart failure.     

Hiccups as a myocardial ischemia symptom

A hiccup is involuntary, paroxysmal inspiratory movements of the chest wall associated with diaphragm and accessory respiratory muscle contractions, with the synchronized closure of glottis. The mechanism underlying this common primitive reflex plays an important role in protecting airways against esophageal aspiration. The hiccup reflex mechanism is based on the afferent pathway (vagus and phrenic nerve and sympathetic fibers innervating chest organs, the abdomen, the ear, the nose and the throat stimulation, and the stimulation of hiccup center in the central nervous system, mainly reflecting psychogenic or metabolic disorders) and the efferent pathway (phrenic nerves). An incidental hiccup is a common problem, usually resolves spontaneously and does not present a clinical issue. The clinical issue arises in the case of pathologic persistent hiccups or symptomatic secondary hiccups which may lead to significant fatigue, insomnia or depression. Generally, pathologic hiccups are associated with considerable discomfort concerning both the "stigmatized" person and his or her personal surroundings in which it evokes different emotions, from amusement through impatience to uneasiness and the suggestion of a medical visit as an expression of concern for a given person. The most common causes of pathologic symptomatic hiccups are nervous system diseases, either the central nervous system (proliferative, angiogenic, inflammatory disorders), or the peripheral nervous system: the irritation of the phrenic nerve (proliferative disorders, goitre) and the vagus nerve (otolaryngologic diseases, meningitis, esophageal, stomach and duodenal diseases, hepatitis, pancreatitis, enteritis). The vagus nerve irritation with subsequent hiccups may be caused by chest disorders (injury, surgery) and heart diseases (myocardial infarction). In the present paper we describe the case of a 62-year-old male with recurrent hiccups associated with exertion as a secondary symptom of myocardial ischemia.     

Exercise training in heart failure

The reduction of exercise capacity with early occurrence of fatigue and dyspnea is a hallmark of heart failure syndrome. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism, and function are present. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training also in heart failure.     

Exercise training in heart failure

The reduction of exercise capacity with early occurrence of fatigue and dyspnea is a hallmark of heart failure syndrome. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism, and function are present. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training also in heart failure.     

Central fatigue of the rabbit diaphragm

This study evaluates the importance of central fatigue of the diaphragm in rabbits subjected to inspiratory muscle resistive loading (IRL). Ten rabbits were subjected to constant IRL while unanesthetized and breathing supplemental oxygen. During 10-20 minutes of spontaneous breathing against IRL, there were no significant changes in arterial oxygen saturation or in diaphragm contractility, measured by the quasi-static transdiaphragmatic pressure response to a 0.3-sec train of 100 Hz supramaximal phrenic nerve stimuli. After an initial decrease due to application of the load, the minute ventilation decreased further, by an average of 15%, while arterial pCO2 increased to an average of 59 mmHg (p less than 0.05). The normalized diaphragm pressure-time index initially increased from 0.02 to 0.18 during IRL, then decreased an average of 29% (p less than 0.05). These results show that severe IRL causes a decrease in the level of diaphragmatic effort over time despite increased chemical drive and despite a preserved ability of the muscle to respond to phrenic nerve stimuli. This adaptation may help to prevent peripheral diaphragm fatigue.     

Exercise as a treatment modality for congestive heart failure

Chronic congestive heart failure is a clinical syndrome that affects nearly 5 million people in the United States alone. Patients with this condition have symptoms of dyspnea and exertional fatigue that often limit their daily activities and decrease their quality of life. There has recently been a paradigm shift in the management of congestive heart failure. Current strategies are focusing on improving the central cardiopulmonary abnormalities, such as decreased ejection fraction and increased capillary wedge pressure, and interventions aimed at improving the numerous peripheral changes that occur with congestive heart failure. Exercise as a treatment modality has been shown to affect many of these peripheral changes, specifically abnormalities in the skeletal muscle, peripheral blood flow, and neurohormonal milieu, which improve with appropriate exercise regimes. Exercise also reduces the symptoms of exertional fatigue, improves quality of life, and increases survival. This article reviews the current experience with exercise and congestive heart failure and discusses strategies used to implement an exercise program for patients.     

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.     

Differences in pulmonary and extra-pulmonary characteristics in severely versus non-severely fatigued recipients of allogeneic hematopoietic stem cell transplantation: a cross-sectional,comparative study

Objectives: Fatigue is a common symptom in allogeneic-hematopoietic stem cell transplantation (allogeneic-HSCT) recipients. However, effects of severe fatigue on pulmonary functions, blood cells, dyspnea, muscle strength, exercise capacity, depression and quality of life (QOL) in allogeneic-HSCT recipients are still unknown. Therefore, to compare pulmonary functions, blood levels, dyspnea, muscle strength, exercise capacity, depression, and QOL between allogeneic-HSCT recipients according to fatigue severity and to determine predictors of severe fatigue were aimed in the current study.

Methods: Twenty-four severe-fatigued (Fatigue Severity Scale score ≥36) (40.08?±?12.44years) and 25 non-severe-fatigued (36.20?±?13.73years) allogeneic-HSCT recipients were compared. Blood levels, pulmonary functions (spirometer), dyspnea (Modified Medical Research Council Dyspnea scale), exercise capacity (6-minute walk test), depression (Beck Depression Inventory-II), QOL (European Organization for Research and Treatment of Cancer QOL Questionnaire), respiratory (mouth pressure device) and peripheral muscle strength (dynamometer) were evaluated.

Results: Symptom QOL-subscale and depression scores were significantly higher; peripheral muscle strength, global health status, and functional QOL-subscales scores were lower in severe-fatigued recipients (p?<?0.05) whose exercise capacity was clinically (28.85?m) decreased. Blood levels, pulmonary functions, dyspnea, and respiratory muscle strength were similar in groups (p?>?0.05). 42.4% of the variance in severe fatigue was explained by symptom QOL-subscale score and corticosteroid use after HSCT (p?<?0.001).

Conclusions: Impairments in peripheral muscle strength, QOL, exercise capacity, and depression are more prevalent among severe-fatigued recipients. Moreover, poorer QOL and corticosteroid use after HSCT are most important predictors of severe fatigue. Effects of comprehensive exercise programs and psychosocial support for severe-fatigued recipients in late post-engraftment period should be investigated.     

Central fatigue of the rabbit diaphragm

This study evaluates the importance of central fatigue of the diaphragm in rabbits subjected to inspiratory muscle resistive loading (IRL). Ten rabbits were subjected to constant IRL while unanesthetized and breathing supplemental oxygen. During 10–20 minutes of spontaneous breathing against IRL, there were no significant changes in arterial oxygen saturation or in diaphragm contractility, measured by the quasi-static transdiaphragmatic pressure response to a 0.3-sec train of 100 Hz supramaximal phrenic nerve stimuli. After an initial decrease due to application of the load, the minute ventilation decreased further, by an average of 15%, while arterial pCO₂ increased to an average of 59 mmHg (p < 0.05). The normalized diaphragm pressure-time index initially increased from 0.02 to 0.18 during IRL, then decreased an average of 29% (p < 0.05). These results show that severe IRL causes a decrease in the level of diaphragmatic effort over time despite increased chemical drive and despite a preserved ability of the muscle to respond to phrenic nerve stimuli. This adaptation may help to prevent peripheral diaphragm fatigue.     

Bedside‐to‐Bench Conference: Research Agenda for Idiopathic Fatigue and Aging

The American Geriatrics Society, with support from the National Institute on Aging and the John A. Hartford Foundation, held its fifth Bedside‐to‐Bench research conference, “Idiopathic Fatigue and Aging,” to provide participants with opportunities to learn about cutting‐edge research developments, draft recommendations for future research, and network with colleagues and leaders in the field. Fatigue is a symptom that older persons, especially by those with chronic diseases, frequently experience. Definitions and prevalence of fatigue may vary across studies, across diseases, and even between investigators and patients. The focus of this review is on physical fatigue, recognizing that there are other related domains of fatigue (such as cognitive fatigue). Many definitions of fatigue involve a sensation of “low” energy, suggesting that fatigue could be a disorder of energy balance. Poor energy utilization efficiency has not been considered in previous studies but is likely to be one of the most important determinants of fatigue in older individuals. Relationships between activity level, capacity for activity, a tolerable rate of activity, and a tolerable fatigue threshold or ceiling underlie a notion of fatiguability. Mechanisms probably contributing to fatigue in older adults include decline in mitochondrial function, alterations in brain neurotransmitters, oxidative stress, and inflammation. The relationships between muscle function and fatigue are complex. A number of diseases (such as cancer) are known to cause fatigue and may serve as models for how underlying impaired physiological processes contribute to fatigue, particularly those in which energy utilization may be an important factor. A further understanding of fatigue will require two key strategies: to develop and refine fatigue definitions and measurement tools and to explore underlying mechanisms using animal and human models.     

Fatigue in chronic liver disease: New insights and therapeutic approaches

The management of fatigue associated with chronic liver disease is a complex and major clinical challenge. Although fatigue can complicate many chronic diseases, it is particularly common in diseases with an inflammatory component. Fatigue can have both peripheral (i.e., neuromuscular) and central (i.e., resulting from changes in neurotransmission within the brain) causes. However, fatigue in chronic liver disease has strong social/contextual components and is often associated with behavioural alterations including depression and anxiety. Given the increasing awareness of patient‐reported outcomes as important components of treatment outcomes and clinical research, there is a growing need to better understand and manage this poorly understood yet debilitating symptom. Although several pathophysiological mechanisms for explaining the development of fatigue have been generated, our understanding of fatigue in patients with chronic liver disease remains incomplete. A better understanding of the pathways and neurotransmitter systems involved may provide specific directed therapies. Currently, the management of fatigue in chronic liver disease can involve a combined use of methods to beneficially alter behavioural components and pharmacological interventions, of which several treatments have potential for the improved management of fatigue in chronic liver disease. However, evidence and consensus are lacking on the best approach and the most appropriate biochemical target(s) whilst clinical trials to address this issue have been few and limited by small sample size. In this review, we outline current understanding of the impact of fatigue and related symptoms in chronic liver disease, discuss theories of pathogenesis, and examine current and emerging approaches to its treatment.