Effect of tamoxifen on fatty degeneration and atrophy of rotator cuff muscles in chronic rotator cuff tear: An animal model study.

Fatty degeneration of the rotator cuff muscles is an irreversible change resulting from chronic rotator cuff tear and is associated with poor clinical outcomes following rotator cuff repair. We evaluated the effect of Tamoxifen, a competitive estrogen receptor inhibitor, on fatty degeneration using a mouse model for chronic rotator cuff tear. Sixteen adult mice were divided into two diet groups (Tamoxifen vs.

Alcohol Differentially Alters Extracellular Matrix and Adhesion Molecule Expression in Skeletal Muscle and Heart.

Background: The production of fibrosis in response to chronic alcohol abuse is well recognized in liver but has not been fully characterized in striated muscle and may contribute to functional impairment. Therefore, the purpose of this study was to use an unbiased discovery-based approach to determine the effect of chronic alcohol consumption on the expression profile of genes important for cell-cell and cell-extracellular matrix (ECM) interactions in both skeletal and cardiac muscle.

Methods: Adult male rats were pair-fed an alcohol-containing liquid diet or control diet for 24 weeks, and skeletal muscle (gastrocnemius) and heart were collected in the freely fed state.

Sepsis-induced changes in amino acid transporters and leucine signaling via mTOR in skeletal muscle.

The present study tested the hypothesis that sepsis-induced leucine (Leu) resistance in skeletal muscle is associated with a down-regulation of amino acid transporters important in regulating Leu flux or an impairment in the formation of the Leu-sensitive mTOR-Ragulator complex. Sepsis in adult male rats decreased basal protein synthesis in gastrocnemius, associated with a reduction in mTOR activation as indicated by decreased 4E-BP1 and S6K1 phosphorylation. The ability of oral Leu to increase protein synthesis and mTOR kinase after 1 h was largely prevented in sepsis.

Disruption of genes encoding eIF4E binding proteins-1 and -2 does not alter basal or sepsis-induced changes in skeletal muscle protein synthesis in male or female mice.

Sepsis decreases skeletal muscle protein synthesis in part by impairing mTOR activity and the subsequent phosphorylation of 4E-BP1 and S6K1 thereby controlling translation initiation; however, the relative importance of changes in these two downstream substrates is unknown. The role of 4E-BP1 (and -BP2) in regulating muscle protein synthesis was assessed in wild-type (WT) and 4E-BP1/BP2 double knockout (DKO) male mice under basal conditions and in response to sepsis. At 12 months of age, body weight, lean body mass and energy expenditure did not differ between WT and DKO mice.

Chronic α-hydroxyisocaproic acid treatment improves muscle recovery after immobilization-induced atrophy.

Muscle disuse atrophy is observed routinely in patients recovering from traumatic injury and can be either generalized resulting from extended bed rest or localized resulting from single-limb immobilization. The present study addressed the hypothesis that a diet containing 5% α-hydroxyisocaproic acid (α-HICA), a leucine (Leu) metabolite, will slow the loss and/or improve recovery of muscle mass in response to disuse. Adult 14-wk-old male Wistar rats were provided a control diet or an isonitrogenous isocaloric diet containing either 5% α-HICA or Leu.

Aging accentuates alcohol-induced decrease in protein synthesis in gastrocnemius.

The present study sought to determine whether the protein catabolic response in skeletal muscle produced by chronic alcohol feeding was exaggerated in aged rats. Adult (3 mo) and aged (18 mo) female F344 rats were fed a nutritionally complete liquid diet containing alcohol (36% of total calories) or an isocaloric isonitrogenous control diet for 20 wk. Muscle (gastrocnemius) protein synthesis, as well as mTOR and proteasome activity did not differ between control-fed adult and aged rats, despite the increased TNF-α and IL-6 mRNA and decreased IGF-I mRNA in muscle of aged rats.

Direct central nervous system effect of alcohol alters synthesis and degradation of skeletal muscle protein.

Aims: Alcohol can directly impair protein synthesis in cultured myocytes as well as in in situ perfused skeletal muscle. However, alcohol in the general circulation diffuses rapidly into the central nervous system (CNS). Therefore, this study determined whether localized elevation of alcohol within the CNS is capable of decreasing muscle protein synthesis.

Sepsis-induced alterations in protein-protein interactions within mTOR complex 1 and the modulating effect of leucine on muscle protein synthesis.

Sepsis-induced muscle atrophy is produced in part by decreased protein synthesis mediated by inhibition of mTOR (mammalian target of rapamycin). The present study tests the hypothesis that alteration of specific protein-protein interactions within the mTORC1 (mTOR complex 1) contributes to the decreased mTOR activity observed after cecal ligation and puncture in rats. Sepsis decreased in vivo translational efficiency in gastrocnemius and reduced the phosphorylation of eukaryotic initiation factor (eIF) 4E-binding protein (BP) 1, S6 kinase (S6K) 1, and mTOR, compared with time-matched pair-fed controls.

Alcohol and PRAS40 knockdown decrease mTOR activity and protein synthesis via AMPK signaling and changes in mTORC1 interaction.

The mTORC1 protein kinase complex consists of mTOR, raptor, mLST8/GbetaL and PRAS40. Previously, we reported that mTOR plays an important role in regulating protein synthesis in response to alcohol (EtOH). However, the mechanisms by which EtOH regulates mTORC1 activity have not been established.

Regulation of REDD1 by insulin-like growth factor-I in skeletal muscle and myotubes.

Insulin-like growth factor-I (IGF-I) is a major anabolic hormone for skeletal muscle and a potent stimulus for protein synthesis and translation initiation. Recent studies suggest that translation can be inhibited by over expression of the mammalian target of rapamycin (mTOR) repressor REDD1. The purpose of the present study was to determine whether IGF-I alters the expression of REDD1 and whether this is associated with a concomitant change in protein synthesis in vitro.

Castration differentially alters basal and leucine-stimulated tissue protein synthesis in skeletal muscle and adipose tissue.

Reduced testosterone as a result of catabolic illness or aging is associated with loss of muscle and increased adiposity. We hypothesized that these changes in body composition occur because of altered rates of protein synthesis under basal and nutrient-stimulated conditions that are tissue specific. The present study investigated such mechanisms in castrated male rats (75% reduction in testosterone) with demonstrated glucose intolerance.

Local insulin-like growth factor I prevents sepsis-induced muscle atrophy.

The present study tests the hypotheses that local bioavailability of insulin-like growth factor I (IGF-I) is capable of regulating muscle protein balance and that muscle-directed IGF-I can selectively maintain muscle mass during bacterial infection. Initial studies in C57BL/6 mice demonstrated that increasing or decreasing bioavailable IGF-I within muscle by local administration of either Leu(24) Ala(31) IGF-I or IGF binding protein 1, respectively, produced proportional changes in surrogate markers (eg, phosphorylation of 4E-BP1 and S6K1) of protein synthesis. We next examined the ability of a sustained local administration of IGF-I to prevent sepsis-induced muscle atrophy over a 5-day period.

Alcohol-induced decrease in muscle protein synthesis associated with increased binding of mTOR and raptor: Comparable effects in young and mature rats.

Background: Acute alcohol (EtOH) intoxication decreases muscle protein synthesis via inhibition of mTOR-dependent translation initiation. However, these studies have been performed in relatively young rapidly growing rats in which muscle protein accretion is more sensitive to growth factor and nutrient stimulation. Furthermore, some in vivo-produced effects of EtOH vary in an age-dependent manner.

Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside prevents leucine-stimulated protein synthesis in rat skeletal muscle.

Several stress conditions are characterized by activation of 5'-AMP-activated protein kinase (AMPK) and the development of leucine resistance in skeletal muscle. In the present study, we determined whether direct activation of the AMPK by 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) prevents the characteristic leucine-induced increase in protein synthesis by altering mammalian target of rapamycin (mTOR) signal transduction. Rats were injected with AICAR or saline (Sal) and 1 h thereafter received an oral gavage of leucine (or Sal).

Skeletal and cardiac myopathy in HIV-1 transgenic rats.

The mechanism by which human immunodeficiency virus (HIV)-1 infection in humans leads to the erosion of lean body mass is poorly defined. Therefore, the purpose of the present study was to determine whether transgenic (Tg) rats that constitutively overexpress HIV-1 viral proteins exhibit muscle wasting and to elucidate putative mechanisms. Over 7 mo, Tg rats gained less body weight than pair-fed controls exclusively as a result of a proportional reduction in lean, not fat, mass.

Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle.

The HIV protease inhibitor indinavir adversely impairs carbohydrate and lipid metabolism, whereas its influence on protein metabolism under in vivo conditions remains unknown. The present study tested the hypothesis that indinavir also decreases basal protein synthesis and impairs the anabolic response to insulin in skeletal muscle. Indinavir was infused intravenously for 4 h into conscious rats, at which time the homeostasis model assessment of insulin resistance was increased.

Alcohol intoxication impairs phosphorylation of S6K1 and S6 in skeletal muscle independently of ethanol metabolism.

Background: The purpose of this study was to characterize the ability of alcohol to suppress insulin-like growth factor (IGF)-I stimulation of ribosomal S6 kinase 1 (S6K1) and 4E-BP1 phosphorylation, which are central elements in the signal transduction pathway used to coordinate the protein synthetic response and may contribute to the development of alcoholic myopathy.

Methods: In vivo studies examined the dose and time dependency of the ability of alcohol to impair signal transduction under basal and IGF-I-stimulated conditions. Additional studies examined the effect of gender, nutritional state, and route of alcohol administration.

TNFalpha mediates sepsis-induced impairment of basal and leucine-stimulated signaling via S6K1 and eIF4E in cardiac muscle.

Decreased translation initiation adversely impacts protein synthesis and contributes to the myocardial dysfunction produced by sepsis. Therefore, the purpose of the present study was to identify sepsis-induced changes in signal transduction pathways known to regulate translation initiation in cardiac muscle and to determine whether the stimulatory effects of leucine can reverse the observed defects. To address this aim, sepsis was produced by cecal ligation and puncture (CLP) in anesthetized rats and the animals studied in the fasted condition 24 h later.