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Sepsis is a severe infection that is a leading cause of hospitalizations and mortality. It is associated with long-term medical complications, including skeletal muscle weakness, atrophy, and wasting. This is characterized by decreased muscle mass, reduced muscle fiber size, and decreased muscle strength, resulting in persistent physical disability. Sepsis induces a myopathy characterized by reductions in force-generating capacity, atrophy, and altered bioenergetics. It causes sarcolemmal injury in muscles, with diaphragm myofibers demonstrating greater levels of damage than control animals. Sepsis survivors suffer significant weight loss and face long-term disability due to muscle weakness.
| Characteristics | Values |
|---|---|
| Cause | Bacterial infections |
| Risk | Survivors of sepsis are at risk of developing persistent acquired weakness syndromes affecting both the respiratory muscles and the limb muscles |
| Muscle weakness | Survivors of sepsis suffer from long-term muscle weakness, including skeletal muscle weakness |
| Muscle wasting | Sepsis-associated muscle wasting (SAMW) is characterised by decreased muscle mass, reduced muscle fibre size, and decreased muscle strength |
| Muscle atrophy | Sepsis patients often develop muscle atrophy that can last for years |
| Muscle regeneration | Sepsis impairs muscle regeneration |
| Mitochondrial abnormalities | Mitochondrial abnormalities are present in the skeletal muscle of sepsis survivors |
| Mortality | Sepsis is associated with mortality in 60% of cases |
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What You'll Learn
Sepsis-associated muscle wasting (SAMW)
Sepsis is a severe impairment of organ function caused by an unbalanced immune response to bacterial infection. It is the leading cause of in-patient hospitalisation. Most sepsis survivors suffer from long-term medical complications, including sepsis-associated muscle wasting (SAMW).
SAMW is characterised by decreased muscle mass, reduced muscle fibre size, and decreased muscle strength, resulting in persistent physical disability. It occurs in 40-70% of patients with sepsis. The main cause of SAMW is systemic inflammatory cytokines, which activate the ubiquitin-proteasome, calpain, and autophagy signalling pathways. This results in protein degradation overwhelming protein synthesis, leading to muscle wasting.
The tibialis anterior muscle has been found to be the most easily influenced muscle during sepsis and underlying sepsis-related muscle wasting. SAMW can be detected as early as two days after the onset of sepsis, whereas disuse muscle atrophy takes at least a week to be detected. Type II fibres are more affected than Type I in SAMW, whereas disuse of muscles more easily affects Type I fibres.
In clinical settings, electrical muscular stimulation, physiotherapy, early mobilisation, and nutritional support are used to prevent or treat SAMW. However, there are currently no pharmacological treatments for SAMW, and the underlying mechanisms are still not fully understood.
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Sepsis-induced myopathy
Sepsis is a major cause of morbidity and mortality in critically ill patients, and survivors often suffer from long-term medical complications, including sepsis-induced myopathy. This condition is characterised by skeletal muscle weakness, atrophy (loss of muscle mass), and altered bioenergetics. Sepsis induces derangements at multiple subcellular sites involved in excitation-contraction coupling, decreasing membrane excitability, injuring sarcolemmal membranes, altering calcium homeostasis, and disrupting contractile protein interactions.
The most accepted model for the origin of SIM suggests that it is triggered by circulating pathogens and cytokines that signal skeletal muscle pathways associated with halted protein synthesis (due to overproduction of reactive oxygen species) and accelerated protein degradation (due to enhanced proteasome proteolytic degradation and autophagy pathways). The activation of these pathways leads to decreased muscle mass and likely results in the loss of force production. In addition, sepsis produces marked abnormalities in muscle mitochondrial functional capacity, and when severe, these alterations correlate with increased mortality.
Studies have shown that sepsis induces more abundant cytokine levels in the diaphragm compared to limb muscle, indicating that respiratory muscles may be more susceptible to sepsis-induced injury. If this is the case, respiratory muscle weakness may represent the earliest manifestation of SIM. Furthermore, muscle wasting occurs later and results from increased proteolytic degradation and decreased protein synthesis.
There is currently no consensus on effective rehabilitation strategies for sepsis-induced myopathy, and the optimal timing to initiate rehabilitation intervention is yet to be determined. However, physical rehabilitation has emerged as a potential tool to prevent the decline in physical function in septic patients.
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Muscle weakness and atrophy
Sepsis is a severe infection that is the leading cause of hospital admissions. It is associated with high mortality and morbidity rates. Sepsis survivors often suffer from long-term medical complications, including muscle weakness and atrophy, also known as sepsis-associated muscle wasting (SAMW). SAMW is characterised by decreased muscle mass, reduced muscle fibre size, and decreased muscle strength, resulting in persistent physical disability. This muscle weakness and atrophy can last for years.
Muscle wasting occurs as a physiological response to ageing and systematic diseases, including sepsis. In skeletal muscle, three major pathways are involved in muscle wasting: the ubiquitin-proteasome system, the calpain system, and autophagy. The ubiquitin-proteasome system plays a key role in muscle mass loss through the upregulation of ubiquitin-conjugating enzymes (E2) and ubiquitin-protein ligases (E3). The first muscle-specific ubiquitin ligases discovered were Muscle Atrophy Gene-1 (Atrogin-1) and Muscle Ring Finger-1 (MuRF1), which are now key target genes for muscle wasting. The calpain system, meanwhile, is involved in myofibrillar protein consumption and belongs to the calcium-dependent cysteine protease family. Finally, autophagy is triggered at the onset of sepsis, indicating that muscular atrophy results in significant type II fibre atrophy. Type II fibres use sugars such as glycogen as an energy source, and high carbohydrate intake may increase the recovery rate from type II fibre loss.
In addition to muscle wasting, sepsis induces a myopathy characterised by reductions in force-generating capacity, atrophy, 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, and disrupting contractile protein interactions. Sepsis also causes sarcolemmal injury in muscles, which has been linked to excessive nitric oxide generation and alterations in diaphragm myofibre membrane potential.
The development of muscle weakness and atrophy in sepsis patients has been linked to mitochondrial abnormalities and dysfunction. Studies have shown that sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction. This dysfunction impairs muscle regeneration, leading to inefficient muscle regeneration and prolonged muscle weakness. However, the relationship between abnormal mitochondria and muscle weakness is not yet fully understood, and further research is needed.
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Muscle wasting and weight loss
Sepsis is a severe infection that causes an uncontrolled systemic inflammatory response, leading to tissue damage and multiple organ failure. It is the leading cause of inpatient hospitalisations and has a high mortality rate. Sepsis survivors often suffer from long-term medical complications, including muscle wasting and weight loss.
The catabolism of skeletal muscle in the early phases of sepsis can be beneficial as it provides glutamine and amino acids to the body. However, if this catabolic activity persists, it leads to muscle loss. Continued loss of muscle proteins, particularly myofibrillar proteins, results in muscle atrophy and weakness. Sepsis also causes sarcolemmal injury in muscles, which can be prevented with mechanical ventilation.
Critical illness myopathy (CIM) is a major complication of sepsis, affecting up to 4% of septic patients and resulting in increased mortality and long-term disability. CIM is characterised by membrane excitability impairment, energetic impairment, proteolysis, and intracellular calcium homeostasis disturbance, leading to muscle weakness and wasting. The muscle weakness, wasting, and fatigue associated with CIM can persist for up to five years, significantly impacting functional status and quality of life.
Currently, there are no pharmacological treatments for SAMW. However, clinical interventions such as electrical muscular stimulation, physiotherapy, early mobilisation, and nutritional support are used to prevent and treat SAMW in sepsis patients. Mesenchymal stem cell therapy has also been shown to improve muscle strength and regeneration in sepsis survivors.
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Impaired muscle regeneration
Sepsis is a severe infection that affects multiple organs and is the leading cause of hospital admissions. It is associated with high mortality and morbidity rates. Survivors of sepsis suffer from long-term complications, including skeletal muscle weakness, muscle atrophy, and impaired muscle regeneration.
Muscle regeneration depends on muscle stem cells, also known as satellite cells (SCs). SCs are activated in response to muscle injury, proliferating and differentiating to repair or replace damaged muscle fibres. However, in the context of sepsis, SC activation, proliferation, and expression of myogenic markers are impaired, leading to impaired muscle regeneration. This impairment has been observed in murine models of sepsis, specifically in the case of polymicrobial peritonitis.
Recent studies have shown that the administration of exogenous mesenchymal stem cells (MSCs) can reverse SC dysfunction and improve muscle regeneration in septic conditions. MSC treatment has been found to decrease necrosis and fibrosis while increasing the force of isolated muscle fibres. This treatment has also been shown to restore mitochondrial and metabolic function in satellite cells, improving muscle strength.
The pathophysiology of sepsis-induced muscle weakness is complex and involves multiple mechanisms. Sepsis induces a myopathy characterized by reductions in force-generating capacity, atrophy (loss of muscle mass), and altered bioenergetics. It causes sarcolemmal injury in muscles, decreasing membrane excitability, altering calcium homeostasis, and disrupting contractile protein interactions. Sepsis also leads to mitochondrial abnormalities in skeletal muscles, although the exact relationship between abnormal mitochondria and muscle weakness is not yet fully understood.
In summary, sepsis is a severe condition that can lead to long-term muscle weakness and impaired muscle regeneration. While the underlying mechanisms are multifaceted, recent advancements in mesenchymal stem cell therapy offer promising interventions to improve muscle recovery and regeneration in septic patients.
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Frequently asked questions
Yes, sepsis causes muscle wasting and muscle weakness.
Sepsis causes muscle loss through muscle atrophy, which occurs due to inactivity or denervation. Sepsis also alters protein synthesis in skeletal muscle, decreasing it by 50% in hind-limb muscles.
Sepsis causes muscle weakness by impairing muscle regeneration. It does so by affecting the function and energy metabolism of satellite cells, which are essential for skeletal muscle regeneration.
Muscle weakness caused by sepsis can be prevented by pharmacological protection of mitochondria. Mesenchymal stem cell therapy has also been shown to improve muscle strength in sepsis patients by restoring mitochondrial and metabolic function in satellite cells.
