Idiopathic inflammatory myopathies: one year in review 2022.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of disorders in which chronic inflammation of the skeletal muscle, leading to muscle weakness, is a common feature. Different phenotypes have been identified within the IIM spectrum based on extra-muscular manifestations, immunology, muscle histology, responsiveness to therapy, and prognosis. The pathogenesis, classification, treatment, and prognosis of the different IIM subtypes are subject to active discussion and research. This review highlights the most relevant literature published on this topic over the last year.

Sarcopenia - Definition, Radiological Diagnosis, Clinical Significance. / Sarkopenie ­ Definition, radiologische Erfassung, klinische Bedeutung.

BACKGROUND: Sarcopenia is an age-related syndrome characterized by a loss of muscle mass and strength. As a result, the independence of the elderly is reduced and the hospitalization rate and mortality increase. The onset of sarcopenia often begins in middle age due to an unbalanced diet or malnutrition in association with a lack of physical activity. This effect is intensified by concomitant diseases such as obesity or metabolic diseases including diabetes mellitus. METHOD: With effective preventative diagnostic procedures and specific therapeutic treatment of sarcopenia, the negative effects on the individual can be reduced and the negative impact on health as well as socioeconomic effects can be prevented. Various diagnostic options are available for this purpose. In addition to basic clinical methods such as measuring muscle strength, sarcopenia can also be detected using imaging techniques like dual X-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), and sonography. DXA, as a simple and cost-effective method, offers a low-dose option for assessing body composition. With cross-sectional imaging techniques such as CT and MRI, further diagnostic possibilities are available, including MR spectroscopy (MRS) for noninvasive molecular analysis of muscle tissue. CT can also be used in the context of examinations performed for other indications to acquire additional parameters of the skeletal muscles (opportunistic secondary use of CT data), such as abdominal muscle mass (total abdominal muscle area - TAMA) or the psoas as well as the pectoralis muscle index. The importance of sarcopenia is already well studied for patients with various tumor entities and also infections such as SARS-COV2. RESULTS AND CONCLUSION: Sarcopenia will become increasingly important, not least due to demographic changes in the population. In this review, the possibilities for the diagnosis of sarcopenia, the clinical significance, and therapeutic options are described. In particular, CT examinations, which are repeatedly performed on tumor patients, can be used for diagnostics. This opportunistic use can be supported by the use of artificial intelligence. KEY POINTS: · Sarcopenia is an age-related syndrome with loss of muscle mass and strength.. · Early detection and therapy can prevent negative effects of sarcopenia.. · In addition to DEXA, cross-sectional imaging techniques (CT, MRI) are available for diagnostic purposes.. · The use of artificial intelligence (AI) offers further possibilities in sarcopenia diagnostics.. CITATION FORMAT: · Vogele D, Otto S, Sollmann N et al. Sarcopenia - Definition, Radiological Diagnosis, Clinical Significance. Fortschr Röntgenstr 2023; 195: 393 - 405.

Quantitative muscle magnetic resonance imaging depicts microstructural abnormalities but no signs of inflammation or dystrophy in post-COVID-19 condition.

BACKGROUND AND PURPOSE: Post-COVID-19 condition (PCC) has high impact on quality of life, with myalgia and fatigue affecting at least 25% of PCC patients. This case-control study aims to noninvasively assess muscular alterations via quantitative muscle magnetic resonance imaging (MRI) as possible mechanisms for ongoing musculoskeletal complaints and premature exhaustion in PCC. METHODS: Quantitative muscle MRI was performed on a 3 Tesla MRI scanner of the whole legs in PCC patients compared to age- and sex-matched healthy controls, including a Dixon sequence to determine muscle fat fraction (FF), a multi-echo spin-echo sequence for quantitative water mapping reflecting putative edema, and a diffusion-weighted spin-echo echo-planar imaging sequence to assess microstructural alterations. Clinical examination, nerve conduction studies, and serum creatine kinase were performed in all patients. Quantitative muscle MRI results were correlated to the results of the 6-min walk test and standardized questionnaires assessing quality of life, fatigue, and depression. RESULTS: Twenty PCC patients (female: n = 15, age = 48.8 ± 10.1 years, symptoms duration = 13.4 ± 4.2 months, body mass index [BMI] = 28.8 ± 4.7 kg/m2 ) were compared to 20 healthy controls (female: n = 15, age = 48.1 ± 11.1 years, BMI = 22.9 ± 2.2 kg/m2 ). Neither FF nor T2 revealed signs of muscle degeneration or inflammation in either study groups. Diffusion tensor imaging (DTI) revealed reduced mean, axial, and radial diffusivity in the PCC group. CONCLUSIONS: Quantitative muscle MRI did not depict any signs of ongoing inflammation or dystrophic process in the skeletal muscles in PCC patients. However, differences observed in muscle DTI depict microstructural abnormalities, which may reflect potentially reversible fiber hypotrophy due to deconditioning. Further longitudinal and interventional studies should prove this hypothesis.

Chronic inflammatory demyelinating polyradiculoneuropathy-associated tremor: Phenotype and pathogenesis.

BACKGROUND AND PURPOSE: Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP-related tremor is more variable than other tremor disorders. METHODS: Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross-sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t-test was used for comparisons between groups. RESULTS: Twenty-four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high-frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F-wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor. CONCLUSIONS: Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat-to-beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor.

Recent advances in cell-based and cell-free therapeutic approaches for sarcopenia.

Sarcopenia is a progressive loss of muscle mass and function that is connected with increased hospital expenditures, falls, fractures, and mortality. Although muscle loss has been related to aging, injury, hormonal imbalances, and diseases such as malignancies, chronic obstructive pulmonary disease, heart failure, and kidney failure, the underlying pathogenic mechanisms of sarcopenia are unclear. Exercise-based interventions and multimodal strategies are currently being considered as potential therapeutic approaches to prevent or treat these diseases. Although drug therapy research is ongoing, no drug has yet been proven to have a substantial safety and clinical value to be the first drug therapy to be licensed for sarcopenia. To better understand the molecular alterations underlying sarcopenia and effective treatments, we review leading research and available findings from the systemic change to the muscle-specific microenvironment. Furthermore, we explore possible mechanisms of sarcopenia and provide new knowledge for the development of novel cell-free and cell-based therapeutics. This review will assist researchers in developing better therapies to improve muscle health in the elderly.

The Cytokine Growth Differentiation Factor-15 and Skeletal Muscle Health: Portrait of an Emerging Widely Applicable Disease Biomarker.

Growth differentiation factor 15 (GDF-15) is a stress-induced transforming growth factor-ß superfamily cytokine with versatile functions in human health. Elevated GDF-15 blood levels associate with multiple pathological conditions, and are currently extensively explored for diagnosis, and as a means to monitor disease progression and evaluate therapeutic responses. This review analyzes GDF-15 in human conditions specifically focusing on its association with muscle manifestations of sarcopenia, mitochondrial myopathy, and autoimmune and viral myositis. The use of GDF-15 as a widely applicable health biomarker to monitor muscle disease is discussed, and its potential as a therapeutic target is explored.

Low thoracic skeletal muscle index is associated with negative outcomes in 244 patients with respiratory COVID-19.

BACKGROUND: Sarcopenia is associated with negative outcomes in intensive care unit (ICU) patients and during chronic diseases. We aimed to evaluate if low skeletal muscle index (SMI) measured by computed tomography (CT) at the thoracic level is associated with poor outcomes in hospitalized patients with respiratory COVID-19. METHODS: Patients admitted to the hospital between March 1st and June 9, 2020 with a confirmed diagnosis of respiratory COVID-19 in the Emergency Department were included in this retrospective cohort study. SMI was assessed from a transverse CT image at the T12 level. We analysed the association between thoracic SMI and mortality, ICU admissions, infections, length of stay and gravity scores. RESULTS: We included 244 patients, whose median age was 62 (20-95) years, mean body mass index was 28,6 kg/m2, and 34% were obese patients. 102 patients (41,8%) had low thoracic SMI. On multivariable analysis, low thoracic SMI was associated with more infections (OR = 1,88 [1,06-2,98]) and increased length of stay (OR = 1,87 [1,14-3,49]) but not with mortality (OR = 1.37 [0.54-3.52]), whereas it was inversely associated with ICU admission (OR = 5,56 [1,96-16,67]. CONCLUSION: Low SMI measured by CT at the thoracic level T12 is associated with negative outcomes in patients with respiratory COVID-19.

Characteristics of Japanese Older Adults Whose Trunk Muscle Mass Decreased during the COVID-19 Pandemic.

The coronavirus (COVID-19) pandemic significantly affected the physical and mental functions in older adults, resulting in "corona-frailty". This 2-year prospective study characterized changes in quantitative measures and corona-frailty among a cohort of community-dwelling older women. Changes were evaluated using face-to-face interactions with 39 Japanese women (mean age: 76.1 ± 5.9) in 2019 (pre-pandemic baseline) and 2021 (follow-up during the pandemic). Quantitative measurements of handgrip strength, walking speed, calf circumference, body composition, and background factors were evaluated. Body weight and trunk muscle mass significantly decreased at follow-up. Multiple regression analysis, using change in trunk muscle mass as the dependent variable and background factors as independent variables, identified that decrease in trunk muscle mass was associated with "being robust at baseline" and answering "Yes" to the question of "Do you go out less frequently compared with last year"? The 2-year trunk muscle mass change for each baseline frailty stage showed a significant decrease only in the robust group (-8.0%). The decrease in trunk muscle mass might be related to pandemic-induced lifestyle restraint, suggesting that robust older adults who are healthy and active should take measures that focus on trunk muscles to avoid "corona-frailty".

What Is in the Myopathy Literature?

ABSTRACT: We cover intensive care unit-acquired neuromuscular disorders associated with coronavirus disease 2019. Outcomes may be worse than expected in these patients, and there is some evidence that coronavirus disease 2019 causes myopathy directly. Corticosteroid regimens in Duchenne muscular dystrophy are addressed including outcomes in pulmonary and cardiac function. A recent article notes a continued diagnostic delay in Duchenne muscular dystrophy. An interesting report of a Canary Islands cohort of patients with oculopharyngeal muscular dystrophy is discussed. Features and clinical pearls related to a series of patients with limb-girdle muscle dystrophy R12 (anoctaminopathy) and a misdiagnosis of idiopathic inflammatory myopathy are provided. The last section on autoimmune myopathy includes articles on clinical and pathologic features associated with myositis-specific antibodies and dermatomyositis, the epidemiology of immune-mediated necrotizing myopathies (IMNMs) in Olmsted County, Minnesota, and features of a German cohort of hydroxy-3-methylglutaryl coenzyme A reductase-associated IMNM. A recent article proposes the benefit of early intravenous immunoglobulin use for adults with IMNM. We also highlight a report of 2 unusual cases of antisignal recognition particle myopathy presenting with asymmetric distal weakness.

Roles of ATP and SERCA in the Regulation of Calcium Turnover in Unloaded Skeletal Muscles: Current View and Future Directions.

A decrease in skeletal muscle contractile activity or its complete cessation (muscle unloading or disuse) leads to muscle fibers' atrophy and to alterations in muscle performance. These changes negatively affect the quality of life of people who, for one reason or another, are forced to face a limitation of physical activity. One of the key regulatory events leading to the muscle disuse-induced changes is an impairment of calcium homeostasis, which leads to the excessive accumulation of calcium ions in the sarcoplasm. This review aimed to analyze the triggering mechanisms of calcium homeostasis impairment (including those associated with the accumulation of high-energy phosphates) under various types of muscle unloading. Here we proposed a hypothesis about the regulatory mechanisms of SERCA and IP3 receptors activity during muscle unloading, and about the contribution of these mechanisms to the excessive calcium ion myoplasmic accumulation and gene transcription regulation via excitation-transcription coupling.

Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology.

BACKGROUND AND PURPOSE: Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue. METHODS: Sixteen patients (mean age = 46 years) with post-COVID-19 complaints of fatigue, myalgia, or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analyzed with light and electron microscopy were taken. RESULTS: Muscle weakness was present in 50% and myopathic electromyography in 75%, and in all patients there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of cytochrome c oxidase activity, subsarcollemmal accumulation, and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T lymphocytes and/or muscle fiber human leukocyte antigen ABC expression. In 75%, capillaries were affected, involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries. CONCLUSIONS: The wide variety of histological changes in this study suggests that skeletal muscles may be a major target of SARS-CoV-2, causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation, and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Because most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

Social Detachment Influenced Muscle Mass and Strength during the COVID-19 Pandemic in Japanese Community-Dwelling Older Women.

Social detachment due to coronavirus disease (COVID-19) has caused a decline in physical activity, leading to sarcopenia and frailty in older adults. This study aimed to compare muscle mass, strength, and function values in older women before and after the first wave of the COVID-19 pandemic (April-May 2020). Furthermore, changes in muscle measures across women who experienced different levels of impact on their social participation due to the COVID-19 pandemic were examined. Muscle mass (total, trunk, and appendicular muscle), grip strength, oral motor skills, social interactions (social network and participation), and social support were assessed in 46 Japanese community-dwelling older women (mean, 77.5 y; range 66-93 y) before and after the first wave of the COVID-19 pandemic. Trunk muscle mass significantly decreased after the first wave of the pandemic. When comparing changed values between the enhanced/maintained and reduced group during the pandemic, significant group difference was observed in trunk muscular mass, grip strength, and oral motor skills. Intriguingly, those who enhanced social participation had a positive change of grip strength values, showing that social participation might influence muscle function during the COVID-19 pandemic.

Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review.

Idiopathic inflammatory myopathies (IIM), collectively known as myositis, are a composite group of rare autoimmune diseases affecting mostly skeletal muscle, although other organs or tissues may also be involved. The main clinical feature of myositis is subacute, progressive, symmetrical muscle weakness in the proximal arms and legs, whereas subtypes of myositis may also present with extramuscular features, such as skin involvement, arthritis or interstitial lung disease (ILD). Established subgroups of IIM include dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASyS), overlap myositis (OM) and inclusion body myositis (IBM). Although these subgroups have overlapping clinical features, the widespread variation in the clinical manifestations of IIM suggests different pathophysiological mechanisms. Various components of the immune system are known to be important immunopathogenic pathways in IIM, although the exact pathophysiological mechanisms causing the muscle damage remain unknown. Current treatment, which consists of glucocorticoids and other immunosuppressive or immunomodulating agents, often fails to achieve a sustained beneficial response and is associated with various adverse effects. New therapeutic targets have been identified that may improve outcomes in patients with IIM. A better understanding of the overlapping and diverging pathophysiological mechanisms of the major subgroups of myositis is needed to optimize treatment. The aim of this review is to report on recent advancements regarding DM and IMNM.

Prediction of abdominal CT body composition parameters by thoracic measurements as a new approach to detect sarcopenia in a COVID-19 cohort.

As most COVID-19 patients only receive thoracic CT scans, but body composition, which is relevant to detect sarcopenia, is determined in abdominal scans, this study aimed to investigate the relationship between thoracic and abdominal CT body composition parameters in a cohort of COVID-19 patients. This retrospective study included n = 46 SARS-CoV-2-positive patients who received CT scans of the thorax and abdomen due to severe disease progression. The subcutaneous fat area (SF), the skeletal muscle area (SMA), and the muscle radiodensity attenuation (MRA) were measured at the level of the twelfth thoracic (T12) and the third lumbar (L3) vertebra. Necessity of invasive mechanical ventilation (IMV), length of stay, or time to death (TTD) were noted. For statistics correlation, multivariable linear, logistic, and Cox regression analyses were employed. Correlation was excellent for the SF (r = 0.96) between T12 and L3, and good for the respective SMA (r = 0.80) and MRA (r = 0.82) values. With adjustment (adj.) for sex, age, and body-mass-index the variability of SF (adj. r2 = 0.93; adj. mean difference = 1.24 [95% confidence interval (95% CI) 1.02-1.45]), of the SMA (adj. r2 = 0.76; 2.59 [95% CI 1.92-3.26]), and of the MRA (adj. r2 = 0.67; 0.67 [95% CI 0.45-0.88]) at L3 was well explained by the respective values at T12. There was no relevant influence of the SF, MRA, or SMA on the clinical outcome. If only thoracic CT scans are available, CT body composition values at T12 can be used to predict abdominal fat and muscle parameters, by which sarcopenia and obesity can be assessed.

Evaluation of Muscle Mass and Stiffness with Limb Ultrasound in COVID-19 Survivors.

BACKGROUND: acute illnesses, like COVID-19, can act as a catabolic stimulus on muscles. So far, no study has evaluated muscle mass and quality through limb ultrasound in post-COVID-19 patients. METHODS: cross sectional observational study, including patients seen one month after hospital discharge for SARS-CoV-2 pneumonia. The patients underwent a multidimensional evaluation. Moreover, we performed dominant medial gastrocnemius ultrasound (US) to characterize their muscle mass and quality. RESULTS: two hundred fifty-nine individuals (median age 67, 59.8% males) were included in the study. COVID-19 survivors with reduced muscle strength had a lower muscle US thickness (1.6 versus 1.73 cm, p =0.02) and a higher muscle stiffness (87 versus 76.3, p = 0.004) compared to patients with normal muscle strength. Also, patients with reduced Short Physical Performance Battery (SPPB) scores had a lower muscle US thickness (1.3 versus 1.71 cm, p = 0.01) and a higher muscle stiffness (104.9 versus 81.07, p = 0.04) compared to individuals with normal SPPB scores. The finding of increased muscle stiffness was also confirmed in patients with a pathological value (≥ 4) at the sarcopenia screening tool SARC-F (103.0 versus 79.55, p < 0.001). Muscle stiffness emerged as a significant predictor of probable sarcopenia (adjusted OR 1.02, 95% C.I. 1.002 - 1.04, p = 0.03). The optimal ultrasound cut-offs for probable sarcopenia were 1.51 cm for muscle thickness (p= 0.017) and 73.95 for muscle stiffness (p = 0.004). DISCUSSION: we described muscle ultrasound characteristics in post COVID-19 patients. Muscle ultrasound could be an innovative tool to assess muscle mass and quality in this population. Our preliminary findings need to be confirmed by future studies comparing muscle ultrasound with already validated techniques for measuring muscle mass and quality.

COVID-19-Associated Critical Illness Myopathy with Direct Viral Effects.

Coronavirus disease 2019 (COVID-19) severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2 infection) can lead to intensive care unit (ICU) admission and critical illness myopathy (CIM). We examined 3 ICU patients with COVID-19 who required mechanical ventilation for pneumonia and developed CIM. Pathological examination of the skeletal muscle biopsies revealed myopathic changes consistent with CIM, variable inflammation with autophagic vacuoles, SARS-CoV immunostaining + fibers/granules, and electron microscopy findings of mitochondrial abnormalities and coronavirus-like particles. Although mitochondrial dysfunction with compromised energy production is a critical pathogenic mechanism of non-COVID-19-associated CIM, in our series of COVID-19-associated CIM, myopathic changes including prominent mitochondrial damage suggest a similar mechanism and association with direct SARS-CoV-2 muscle infection. ANN NEUROL 2022;91:568-574.

Thoracic sarcopenia as a predictive factor of SARS-COV2 evolution.

PURPOSE: Evaluation of CT sarcopenia as a predictor of intensive care hospitalization during SARS-COV2 infection. MATERIALS AND METHODS: Single-center retrospective study of patients admitted to hospital with SARS-COV2 infection. The estimation of muscle mass (skeletal muscle index (SMI)) for sarcopenia, measurement of muscle density for muscle quality and body adiposity, were based on CT views on the T4 and L3 levels measured at admission. Demographic data, percentage of pulmonary parenchymal involvement as well as the orientation of patients during hospitalization and the risk of hospitalization in intensive care were collected. RESULTS: A total of 162 patients hospitalized for SARS-COV2 infection were included (92 men and 70 women, with an average age of 64.6 years and an average BMI of 27.4). The muscle area measured at the level of L3 was significantly associated with the patient's unfavorable evolution (124.4cm2 [97; 147] vs 141.5 cm2 [108; 173]) (p = 0.007), as was a lowered SMI (p < 0.001) and the muscle area measured in T4 (OR = 0.98 [0.97; 0.99]), (p = 0.026). Finally, an abdominal visceral fat area measured at the level of L3 was also associated with a risk of hospitalization in intensive care (249.4cm2 [173; 313] vs 147.5cm2 [93.1; 228] (p < 0.001). CONCLUSION: This study demonstrates that thoracic and abdominal sarcopenia are independently associated with an increased risk of hospitalization in an intensive care unit, suggesting the need to assess sarcopenia on admission during SARS-COV2 infection.

Muscle Regeneration and RNA: New Perspectives for Ancient Molecules.

The ability of the ribonucleic acid (RNA) to self-replicate, combined with a unique cocktail of chemical properties, suggested the existence of an RNA world at the origin of life. Nowadays, this hypothesis is supported by innovative high-throughput and biochemical approaches, which definitively revealed the essential contribution of RNA-mediated mechanisms to the regulation of fundamental processes of life. With the recent development of SARS-CoV-2 mRNA-based vaccines, the potential of RNA as a therapeutic tool has received public attention. Due to its intrinsic single-stranded nature and the ease with which it is synthesized in vitro, RNA indeed represents the most suitable tool for the development of drugs encompassing every type of human pathology. The maximum effectiveness and biochemical versatility is achieved in the guise of non-coding RNAs (ncRNAs), which are emerging as multifaceted regulators of tissue specification and homeostasis. Here, we report examples of coding and ncRNAs involved in muscle regeneration and discuss their potential as therapeutic tools. Small ncRNAs, such as miRNA and siRNA, have been successfully applied in the treatment of several diseases. The use of longer molecules, such as lncRNA and circRNA, is less advanced. However, based on the peculiar properties discussed below, they represent an innovative pool of RNA biomarkers and possible targets of clinical value.

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation.

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.