Pathophysiology and Treatment Strategies of Acute Myopathy and Muscle Wasting after Sepsis

Mankowski, Robert T.; Laitano, Orlando; Clanton, Thomas L.; Brakenridge, Scott C.

doi:10.3390/jcm10091874

Cited by 20 publications

(21 citation statements)

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“…Although the universal measurements for sarcopenia remain to be established [ 11 ], sarcopenia has been proposed as a predictor of poor prognosis in patients of various chronic diseases, such as cancer [ 12 ], coronary artery disease [ 13 ], and chronic kidney disease [ 14 ]. Interestingly, patients with sepsis are also vulnerable to muscle catabolism, muscle weakness, and progressive muscle loss with the progression of the disease [ 15 ]. However, previous studies evaluating the association between sarcopenia at admission and mortality risk in patients with sepsis showed inconsistent results [ 16 – 25 ].…”

Section: Introductionmentioning

confidence: 99%

Sarcopenia and Mortality Risk of Patients with Sepsis: A Meta-Analysis

Liu

Zhao

2022

International Journal of Clinical Practice

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Background. The association between sarcopenia at admission and mortality in patients with sepsis has not been comprehensively evaluated. We performed a meta-analysis to systematically evaluate the above association. Methods. This meta-analysis included relevant observational studies from Medline, Embase, and Web of Science databases. A random-effect model after incorporation of the intrastudy heterogeneity was selected to pool the results. Subgroup analyses were applied to evaluate the influences of study characteristics on relationship. Results. Ten cohort studies including 2396 patients with sepsis were included, and 1496 (62.4%) of them had sarcopenia at presentation. Pooled results showed that compared to those without sarcopenia, septic patients with sarcopenia had a significantly increased early (in-hospital or 1-month) mortality risk (risk ration (RR): 2.14, 95% confidence interval (CI): 1.60–2.87, P < 0.001; I2 = 46%). Subgroup analyses showed consistent association between sarcopenia and increased acute mortality risk in septic patients which were not affected by study characteristics such as study design, country of the study, clinical settings, diagnostic criteria for sepsis, age, gender of the patients, and methods for diagnosis of sarcopenia ( P for all subgroup analyses >0.05). Further meta-analyses showed that sarcopenia was also associated with increased mortality risk in septic patients at 3–6 months (RR: 2.13, 95% CI: 1.58–2.89, P < 0.001; I2 = 0%) and at 1 year (RR: 1.57, 95% CI: 1.09–2.24, P = 0.01; I2 = 29%). Conclusions. Current evidence suggests that sarcopenia may be a predictor of mortality in patients with sepsis.

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Section: Introductionmentioning

confidence: 99%

Sarcopenia and Mortality Risk of Patients with Sepsis: A Meta-Analysis

Liu

Zhao

2022

International Journal of Clinical Practice

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“…It is also observed during intentional short-and long-term [2,3] head-down-tilt bed rest, used as space flight analogs to investigate mechanisms and counter measures of muscle atrophy caused by zero gravity. Pathological atrophy is caused by fasting, loss of innervation, due to neurological diseases such as stroke, and in many diseases (e.g., cancer [4], end-stage renal disease [5] and sepsis [6]). Whether or not age-related muscle atrophy can be classified as a physiological or a pathological condition warrants a detailed clinical assessment.…”

Section: Introductionmentioning

confidence: 99%

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

2021

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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.

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“…Rehabilitative strategies to prevent disuse in septic hosts may preserve muscle function (Mankowski et al, 2021), although this may be a challenging intervention in severe septic conditions. Most of our current knowledge about the potential mechanisms underlying sepsis-induced myopathy comes from studies focusing on respiratory muscles in models of endotoxic shock and peritonitis (Maes et al, 2014;Supinski et al, 1985Supinski et al, , 2020.…”

Section: Discussionmentioning

confidence: 99%

The impact of hindlimb disuse on sepsis‐induced myopathy in mice

et al. 2021

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Sepsis induces a myopathy characterized by loss of muscle mass and weakness. Septic patients undergo prolonged periods of limb muscle disuse due to bed rest. The contribution of limb muscle disuse to the myopathy phenotype remains poorly described. To characterize sepsis‐induced myopathy with hindlimb disuse, we combined the classic sepsis model via cecal ligation and puncture (CLP) with the disuse model of hindlimb suspension (HLS) in mice. Male C57bl/6j mice underwent CLP or SHAM surgeries. Four days after surgeries, mice underwent HLS or normal ambulation (NA) for 7 days. Soleus (SOL) and extensor digitorum longus (EDL) were dissected for in vitro muscle mechanics, morphological, and histological assessments. In SOL muscles, both CLP+NA and SHAM+HLS conditions elicited ~20% reduction in specific force (p < 0.05). When combined, CLP+HLS elicited ~35% decrease in specific force (p < 0.05). Loss of maximal specific force (~8%) was evident in EDL muscles only in CLP+HLS mice (p < 0.05). CLP+HLS reduced muscle fiber cross‐sectional area (CSA) and mass in SOL (p < 0.05). In EDL muscles, CLP+HLS decreased absolute mass to a smaller extent (p < 0.05) with no changes in CSA. Immunohistochemistry revealed substantial myeloid cell infiltration (CD68+) in SOL, but not in EDL muscles, of CLP+HLS mice (p < 0.05). Combining CLP with HLS is a feasible model to study sepsis‐induced myopathy in mice. Hindlimb disuse combined with sepsis induced muscle dysfunction and immune cell infiltration in a muscle dependent manner. These findings highlight the importance of rehabilitative interventions in septic hosts to prevent muscle disuse and help attenuate the myopathy.

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Pathophysiology and Treatment Strategies of Acute Myopathy and Muscle Wasting after Sepsis

Cited by 20 publications

References 84 publications

Sarcopenia and Mortality Risk of Patients with Sepsis: A Meta-Analysis

Sarcopenia and Mortality Risk of Patients with Sepsis: A Meta-Analysis

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

The impact of hindlimb disuse on sepsis‐induced myopathy in mice

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