Interleukin-1 receptor antagonist prevents sepsis-induced inhibition of protein synthesis

Cooney, Robert N.; Owens, Erik L.; Jurasinski, C. V.; Gray, Kathleen; Vannice, James L.; Vary, Thomas C.

doi:10.1152/ajpendo.1994.267.5.e636

Cited by 34 publications

(42 citation statements)

References 18 publications

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“…3A). The results are in accordance with previous studies that established that control and septic rats demonstrate reduced food intake for 48 h after surgical implantation of the pellet; however, by 72 h postsurgery, food consumption increases and is not different between septic and control rats (7,56). The demonstrated body mass loss in septic rats on days 3-5 is due to the hyperdynamic, hypermetabolic septic condition.…”

Section: Resultssupporting

confidence: 92%

Ectopic expression of eIF2Bε in rat skeletal muscle rescues the sepsis-induced reduction in guanine nucleotide exchange activity and protein synthesis

Tuckow

Vary

Kimball

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Tuckow AP, Vary TC, Kimball SR, Jefferson LS. Ectopic expression of eIF2Bε in rat skeletal muscle rescues the sepsis-induced reduction in guanine nucleotide exchange activity and protein synthesis. Am J Physiol Endocrinol Metab 299: E241-E248, 2010. First published May 18, 2010; doi:10.1152/ajpendo.00151.2010.-Eukaryotic initiation factor 2B (eIF2B) is a guanine nucleotide exchange factor (GEF) whose activity is both tightly regulated and rate-controlling with regard to global rates of protein synthesis. Skeletal muscle eIF2B activity and expression of its catalytic ε-subunit (eIF2Bε) have been implicated as potential contributors to the altered rates of protein synthesis in a number of physiological conditions and experimental models. The objective of this study was to directly examine the effects of exogenously expressed eIF2Bε in vivo on GEF activity and protein synthetic rates in rat skeletal muscle. A plasmid encoding FLAGeIF2Bε was transfected into the tibialis anterior (TA) of one leg, while the contralateral TA received a control plasmid. Ectopic expression of eIF2Bε resulted in increased GEF activity in TA homogenates of healthy rats, demonstrating that the expressed protein was catalytically active. In an effort to restore a deficit in eIF2B activity, we utilized an established model of chronic sepsis in which skeletal muscle eIF2B activity is known to be impaired. Ectopic expression of eIF2Bε in the TA rescued the sepsis-induced deficit in GEF activity and muscle protein synthesis. The results demonstrate that modulation of eIF2Bε expression may be sufficient to correct deficits in skeletal muscle protein synthesis associated with sepsis and other musclewasting conditions. mRNA translation; in vivo electroporation; muscle wasting SKELETAL MUSCLE exhibits a unique plasticity with regard to its capacity to increase or decrease in size (i.e., hypertrophy or atrophy) in response to a number of nutritional, environmental, and mechanical stimuli. The loss of skeletal muscle mass that occurs in a number of pathophysiological conditions can lead to adverse effects in functional strength and mobility and, in many conditions, is associated with increased morbidity and mortality (e.g., sarcopenia, sepsis, and cancer cachexia) (for reviews see Refs. 2,8,24). In contrast, repetitive application of a mechanical load, such as resistance exercise, leads to a transient shift in the balance between protein synthesis and degradation in favor of net protein synthesis, and thus the cumulative effect of repetitive bouts of resistance exercise is an increase in muscle size (4, 49, 50). To design appropriate therapeutic interventions to ameliorate skeletal muscle atrophy and maintain or increase muscle mass, the mechanisms that regulate skeletal muscle size must be thoroughly understood.In essence, skeletal muscle hypertrophy requires increased rates of protein synthesis relative to rates of protein degradation, such that a net increase in size occurs due to protein accretion (4, 18, 49, 50). The process of protein synthesis...

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Section: Resultssupporting

confidence: 92%

Ectopic expression of eIF2Bε in rat skeletal muscle rescues the sepsis-induced reduction in guanine nucleotide exchange activity and protein synthesis

Tuckow

Vary

Kimball

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…The epitrochlearis was chosen to examine protein turnover after injection of bacteria because previous reports have provided evidence that sepsis preferentially affects protein metabolism in muscles composed of mixed fast-twitch fibers (Hasselgren et al 1989, Vary & Kimball 1992, Cooney et al 1994 and because its size renders it suitable for in vitro incubation. On the day of the experiment, rats were anesthetized with pentobarbital (50 mg/kg body weight).…”

Section: Incubations Of Epitrochlearis Musclesmentioning

confidence: 99%

Pentoxifylline improves insulin action limiting skeletal muscle catabolism after infection

Vary¹,

Dardevet²,

Grizard³

et al. 1999

Journal of Endocrinology

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We investigated the ability of pentoxifylline (PTX) to modulate protein synthesis and degradation in the presence and absence of insulin during incubation of epitrochlearis muscle, 2 or 6 days after injection of Escherichia coli. On days 2 and 6 after infection, protein synthesis was inhibited by 25%, whereas proteolysis was enhanced by 75%. Insulin (2 nM) in vitro stimulated protein synthesis in muscles from infected rats to the same extent as in controls. The ability of insulin to limit protein degradation was severely blunted 48 h after infection. On day 6 after infection, insulin inhibited proteolysis to a greater extent than on day 2. PTX suppressed the increase in plasma concentrations of tumor necrosis factor more than 600-fold after injection of bacteria, and partially prevented the inhibition of protein synthesis and stimulation of protein degradation during sepsis. Moreover, PTX administration maintained the responsiveness of protein degradation to insulin during sepsis. Thus cytokines may influence skeletal muscle protein metabolism during sepsis, both indirectly through inhibition of the effects of insulin on proteolysis, and directly on the protein synthesis and degradation machinery.

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“…Interleukin-1 (IL-1) is a cytokine biomarker that correlates with outcomes in critical illness. In animal models, IL-1 induces muscle atrophy [18] and alters calcium transients in the SR thereby inducing excitation-contraction uncoupling [19]. Genetic manipulation of mitochondrial fission machinery alters mitochondrial morphology, with subsequent dysfunction, energy stress, and downstream activation of muscle atrophy networks [20].…”

mentioning

confidence: 99%

Mechanism of ICU-acquired weakness: muscle contractility in critical illness

2017

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Weakness is common after an episode of critical illness and its associated disability may persist for years, with significant negative impact on the survivor [1]. Strength depends on both the presence and normal function of skeletal muscle, so that either muscle wasting or impaired contractility (muscle-specific force) can induce weakness. This is best appreciated in the gerontology literature where sarcopenia, the concept of which has evolved from simple muscle wasting to loss of muscle mass and function, and dynapenia (loss of strength and power not necessarily associated with loss of muscle mass) are identified and considered separately because they are not synonymous [2]. In aging, the decline in strength exceeds the loss of muscle mass and this is attributed to changes throughout the neuroaxis including those occurring at the peripheral nerve in addition to muscle. Muscle unloading/inactivity in animal models promotes a loss of contractile proteins that exceeds the loss in muscle cell size, resulting in decreased myocyte-specific force [3] and in young adults muscle atrophied by immobilization may recover to regain mass but not strength, reinforcing the notion that, like the dynapenia of aging, muscle strength and mass may be discordant. A pilot study of critical illness-associated weakness also suggests this holds true [4]. Therefore, studies evaluating ICU-acquired weakness (ICUAW) should ensure complete assessment for peripheral neuropathy, neuromuscular junction dysfunction in addition to evaluation for myopathy-loss of muscle mass and deficiency of intrinsic contractility. Although the clinical phenotype may be weakness, the relative contributions of underlying processes and cellular and molecular mechanisms may be very different. This review will focus on the impairment of muscle contractility in critical illness and discuss the responsible muscle-derived cellular and molecular mechanisms.If present, critical illness polyneuropathy or neuromuscular blockade will decrease the force-generating capacity of muscle in the ICU patient. Similarly, myonecrosis and/or altered muscle composition will decrease musclespecific force. Even in the absence of these phenomena cellular signalling within the intact muscle fibers of critically ill patients can impede contractile function directly, with or without concurrent induction of changes in muscle size/mass, at least in the short term. Primary muscle contributions to impaired contractility are multifactorial, but appear to predominantly relate to three fundamental processes: (1) altered muscle membrane excitability, (2) excitation-contraction uncoupling, and (3) altered muscle bioenergetics (Fig. 1). It must be emphasized, however, that most research in these areas has been conducted in animal models of critical illness myopathy (CIM) and sepsis, and is supported by limited evidence from humans.Abnormalities of muscle membrane excitability including decreased conduction velocity, increased relative refractory period, and reduced fiber excitability occur in the cri...

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Interleukin-1 receptor antagonist prevents sepsis-induced inhibition of protein synthesis

Cited by 34 publications

References 18 publications

Ectopic expression of eIF2Bε in rat skeletal muscle rescues the sepsis-induced reduction in guanine nucleotide exchange activity and protein synthesis

Ectopic expression of eIF2Bε in rat skeletal muscle rescues the sepsis-induced reduction in guanine nucleotide exchange activity and protein synthesis

Pentoxifylline improves insulin action limiting skeletal muscle catabolism after infection

Mechanism of ICU-acquired weakness: muscle contractility in critical illness

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