Biomedical subjects

Anthony J Kee

Publications and source records attributed to Anthony J Kee.

9 recordsLinked to original sources

PubMed2005

Does growth hormone allow more efficient nitrogen sparing in postoperative patients requiring parenteral nutrition? A double-blind, placebo-controlled randomised trial.

BACKGROUND & AIMS: Growth hormone (GH) has a strong anabolic effect and is thought to be useful in improving the efficacy of parenteral nutrition (PN) to preserve muscle mass (MM) in the postoperative setting. Unfortunately, the negative clinical outcome of GH treatment in intensive care patients limits its use in this setting, but demands answers to the mechanism behind the action of this therapy. METHOD: In a double-blind randomised controlled study consecutive patients after major abdominal surgery were divided into four groups of either 1/2-PN (0.13 g N/kg/day and 52% of calories as lipid) or full-strength PN (Full-PN) (0.3 g N/kg/day and 65% of calories as lipid) receiving daily injections of either GH (8-16 IU) or placebo for a period of 14 days postoperative. Outcome measures included MM derived from measures of total body potassium (40K counting) and total body nitrogen (TBN) (in vivo neutron capture technique); Fat mass from skin folds; serum insulin like growth factor-I (IGF-I) and its binding proteins (IGFBP). RESULTS: From 43 major upper GI surgical patients randomised 35 completed the study (one patient died from sepsis in the half-strength PN (1/2-PN)+GH group). 1/2-PN (n=11) lost TBN (P=0.001), MM (P=0.005) but not fat. Full-PN (n=9) maintained TBN, MM (P=0.056) and fat. 1/2-PN+GH (n=8) maintained TBN and fat but lost MM (P=0.038). Full-PN+GH (n=7) maintained TBN and MM but lost fat (P=0.018). Two-way ANOVA indicated that PN input (P=0.031) and not GH had a significant effect on MM. GH caused a significant rise in IGF-I levels (290+/-67 and 454+/-71 microg/l for 1/2-PN+GH and Full-PN+GH, respectively) and restored serum IGFBP3 and the acid labile subunit to normal, by the postoperative day 9. CONCLUSION: After major gastrointestinal surgery, GH causes a marked hepatic IGF-I response and nitrogen retention but its effect on body composition was more significant with a high PN input. Further, Full-PN alone was sufficient to prevent nitrogen loss and preserved MM and addition of GH does not provide further metabolic advantage.

Abdomen↗

PubMed2005

Tropomyosin isoforms: divining rods for actin cytoskeleton function.

Actin filament functional diversity is paralleled by variation in the composition of isoforms of tropomyosin in these filaments. Although the role of tropomyosin is well understood in skeletal muscle, where it regulates the actin-myosin interaction, its role in the cytoskeleton has been obscure. The intracellular sorting of tropomyosin isoforms indicated a role in spatial specialization of actin filament function. Genetic manipulation and protein chemistry studies have confirmed that these isoforms are functionally distinct. Tropomyosins differ in their recruitment of myosin motors and their interaction with actin filament regulators such as ADF-cofilin. Tropomyosin isoforms have therefore provided a powerful mechanism to diversify actin filament function in different intracellular compartments.

Actins↗

PubMed2004

Muscle weakness in a mouse model of nemaline myopathy can be reversed with exercise and reveals a novel myofiber repair mechanism.

Patients with the inherited muscle disease nemaline myopathy experience prolonged muscle weakness following periods of immobility. We have examined endurance exercise as a means of improving recovery following muscle inactivity in our alpha-tropomyosin(slow)(Met9Arg)-transgenic mouse model of nemaline myopathy. Physical inactivity, mimicked using a hindlimb immobilization protocol, resulted in fiber atrophy and severe muscle weakness. Following immobilization, the nemaline mice (NM) were weaker than WT mice but regained whole-body strength with exercise training. The disuse-induced weakness and the regain of strength with exercise in NM were associated with the respective formation and resolution of nemaline rods, suggesting a role for rods in muscle weakness. Muscles from NM did not show the typical features of muscle repair during chronic stretch-immobilization of the soleus muscle (regeneration occurred with relative lack of centralized nuclei). This indicates that the normal process of regeneration may be altered in nemaline myopathy and may contribute to poor recovery. In conclusion, endurance exercise can alleviate disuse-induced weakness in NM. The altered myofiber repair process in the nemaline mice may be a response to primary myofibrillar damage that occurs in nemaline myopathy and is distinct from the classical repair in muscular dystrophy resulting from plasma membrane defects.

Animals↗

PubMed2004

Sorting of a nonmuscle tropomyosin to a novel cytoskeletal compartment in skeletal muscle results in muscular dystrophy.

Tropomyosin (Tm) is a key component of the actin cytoskeleton and >40 isoforms have been described in mammals. In addition to the isoforms in the sarcomere, we now report the existence of two nonsarcomeric (NS) isoforms in skeletal muscle. These isoforms are excluded from the thin filament of the sarcomere and are localized to a novel Z-line adjacent structure. Immunostained cross sections indicate that one Tm defines a Z-line adjacent structure common to all myofibers, whereas the second Tm defines a spatially distinct structure unique to muscles that undergo chronic or repetitive contractions. When a Tm (Tm3) that is normally absent from muscle was expressed in mice it became associated with the Z-line adjacent structure. These mice display a muscular dystrophy and ragged-red fiber phenotype, suggestive of disruption of the membrane-associated cytoskeletal network. Our findings raise the possibility that mutations in these tropomyosin and these structures may underpin these types of myopathies.

Animals↗

PubMed2004

Myofiber adaptational response to exercise in a mouse model of nemaline myopathy.

In some muscle diseases, such as muscular dystrophy, exercise can increase muscle damage and alter myofiber adaptation. We determined whether this is also true for the congenital muscle disease nemaline myopathy using our mouse model of this disease. Nemaline mice expressing a mutant alpha-tropomyosinslow protein [alpha-Tmslow(Met9Arg)] in skeletal muscle underwent 4 weeks of treadmill exercise. Exercise increased slow/oxidative myofibers, but different fibers were involved in these transformations in nemaline mice. Despite similar expression of the mutant alpha-Tmslow protein in muscles of the nemaline mouse, muscles responded in a unique manner that did not reflect fiber-type composition. For example, the particular fibers involved in fast-to-slow transformation were specific for each muscle examined. In contrast to the muscular dystrophies, exercise did not result in muscle damage nor did it cause an increase in rod-containing fibers; however, the fiber-type distribution of rod-containing fibers was altered in a muscle-specific fashion. That exercise did not exacerbate the pathology (i.e., nemaline rod formation) supports its use in nemaline myopathy patients. This study shows that fibers of a similar type respond to increased activity differently in different muscles and suggests that fibers of similar type may be functionally distinct in different muscles.

Adaptation, Physiological↗

PubMed2004

A study of parenteral versus enteral nutrition following caecal ligation and puncture in the rat: Influence on survival and tissue protein turnover.

BACKGROUND & AIMS: Methods of nutritional management in abdominal sepsis remain controversial. METHODS: Sprague Dawley rats were either fed via a central line in the right internal jugular vein or duodenally via a gastrostomy tube, and were randomised to undergo either caecal ligation and puncture (CLP) or laparotomy only. Post-operatively, animals received either parenteral nutrition, enteral nutrition or saline only (parenteral and enteral nutrition protocols were isocaloric and isonitrogenous). After 72 h, fractional rate of protein synthesis (Ks, %/day) was measured in gastrocnemius muscle and liver, and protein breakdown was measured in incubated epitrochlearis muscles. Serum insulin-like growth factor-I (IGF-I), acid-labile subunit (ALS) and IGF binding protein-1 (IGFBP-1) levels were determined by specific radioimmunoassay methods. RESULTS: After CLP, when compared with starved animals, only enteral nutrition resulted in a significant decrease in survival to 72 h (P < 0.001). Parenteral nutrition, but not enteral nutrition, increased muscle (P = 0.02) and liver (P < 0.001) Ks, IGF-I (P < 0.001) and ALS levels (P < 0.001), whereas both parenteral and enteral nutrition reduced IGFBP-1 levels (P < 0.001). Neither enteral nor parenteral nutrition reduced protein breakdown in septic animals. CONCLUSIONS: In this model of severe abdominal sepsis where gut function cannot be assessed, enteral nutrition was associated with increased mortality and was less effective than parenteral nutrition in augmenting muscle and liver protein synthesis.

Animals↗

PubMed2003

Ubiquitin-proteasome-dependent muscle proteolysis responds slowly to insulin release and refeeding in starved rats.

The central role of the ubiquitin-proteasome system in the loss of skeletal muscle protein in many wasting conditions has been well established. However, it is unclear what factors are responsible for the suppression of this system during periods of protein gain. Thus, the aim of these studies was to examine the short-term effects of insulin release and nutrients on skeletal muscle protein turnover in young rats starved for 48 h, and then infused intravenously with amino acids (AA), or fed an oral diet. Forty-eight hours of starvation (i.e. prolonged starvation in young rats) decreased muscle protein synthesis and increased proteasome-dependent proteolysis. Four-hour AA infusion and 4 h of refeeding increased plasma insulin release and AA concentrations, and stimulated muscle protein synthesis, but had no effect on either total or proteasome-dependent proteolysis, despite decreased plasma corticosterone concentrations. Both muscle proteasome-dependent proteolysis and the rate of ubiquitination of muscle proteins were not suppressed until 10 h of refeeding. The temporal response of these two measurements correlated with the normalised expression of the 14-kDa E2 (a critical enzyme in substrate ubiquitination in muscle) and the expression of the MSS1 subunit of the 19S regulatory complex of the 26S proteasome. In contrast, the starvation-induced increase in mRNA levels for 20S proteasome subunits was normalised by refeeding within 24 h in muscle, and 6 h in jejunum, respectively. In conclusion, unlike protein synthesis, skeletal muscle proteasome-dependent proteolysis is not acutely responsive in vivo to insulin, AA, and/or nutrient intake in refed starved rats. This suggests that distinct and perhaps independent mechanisms are responsible for the nutrient-dependent regulation of protein synthesis and ubiquitin-proteasome-dependent proteolysis following a prolonged period of catabolism. Furthermore, factors other than the expression of ubiquitin-proteasome pathway components appear to be responsible for the suppression of skeletal muscle proteasome-dependent proteolysis by nutrition.

Amino Acids↗

PubMed2002

IGF-I has no effect on postexercise suppression of the ubiquitin-proteasome system in rat skeletal muscle.

Both exercise and insulin-like growth factor I (IGF-I) are known to have major hypertrophic effects in skeletal muscle; however, the interactive effect of exogenous IGF-I and exercise on muscle protein turnover or the ubiquitin-proteasome pathway has not been reported. In the present study, we have examined the interaction between endurance exercise training and IGF-I treatment on muscle protein turnover and the ubiquitin-proteasome pathway in the postexercise period. Adult male rats (270-280 g) were randomized to receive 5 consecutive days of progressive treadmill exercise and/or IGF-I treatment (1 mg. kg body wt(-1). day(-1)). Twenty-four hours after the last bout of exercise, the rate of protein breakdown in incubated muscles was significantly reduced compared with that in unexercised rats. This was associated with a significant reduction in the chymotrypsin-like activity of the proteasome and the rate of ubiquitin-proteasome-dependent casein hydrolysis in muscle extracts from exercised compared with unexercised rats. In contrast, the muscle expression of the 20S proteasome subunit beta-1, ubiquitin, and the 14-kDa E2 ubiquitin-conjugating enzyme was not altered by exercise or IGF-I treatment 24 h postexercise. Exercise had no effect on the rates of total mixed muscle protein synthesis in incubated muscles 24 h postexercise. IGF-I treatment had no effect on muscle weights or the rates of protein turnover 24 h after endurance exercise. These results suggest that a suppression of the ubiquitin-proteasome proteolytic pathway after endurance exercise may contribute to the acute postexercise net protein gain.

Animals↗

PubMedDate not supplied

Multimodal analgesia and intravenous nutrition preserves total body protein following major upper gastrointestinal surgery.

BACKGROUND AND OBJECTIVES: This study examined whether perioperative multimodal analgesia (MMA) improves the effectiveness of intravenous nutrition (IVN) as a means of preventing protein wasting following major upper abdominal surgery (UAS). The MMA regimen utilized combined epidural opioid/local anesthetic and the systemic nonsteroidal anti-inflammatory drug (NSAID) ketorolac for 48 hours. METHODS: In a prospective, randomized, nonblinded study, 47 patients scheduled for major UAS were allocated to receive the following: MMA +/- intravenous lipid-based nutrition (IVN) or patient-controlled analgesia with opioids (PCA) +/- IVN. Pain scores, nitrogen balance, total body protein (TBP), arterial blood gases, and various hormones were measured. RESULTS: Pain control was significantly better in the MMA patients at rest and coughing. Only the MMA + IVN group maintained TBP, mean (+/-95% confidence interval) preoperative day 1, 10.5 (+/-1.0) kg; day 14, 10.7 (+/-1.2) kg, whereas TBP decreased in the other groups (P =.04). Nitrogen balance was significantly greater in patients receiving IVN on day 7 (P =.01), but there was no effect related to the analgetic regimen. Decreased PaO(2) seen on postoperative day 2 was not prevented by MMA. The hormonal response to surgery was not influenced by treatment modality, apart from a return to postprandial insulin levels on postoperative day 7 in those patients receiving IVN (P =.002). CONCLUSIONS: In conclusion, we have shown that the combination of MMA and IVN prevents protein loss and improves pain control after major UAS. Our results suggest that after UAS, MMA significantly reduced pain and, in combination with IVN, preserves total body protein and fat. This is the first direct evidence of such effects associated with a commonly used multimodal regimen.

Adult↗