Speakers and Topics:

Amino Acids: Regulators of Global and Specific mRNA Translation

Scot R. Kimball

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine

A continuous supply of a complete complement of essential amino acids is a prerequisite for maintenance of optimal rates of protein synthesis in both liver and skeletal muscle. Deprivation of even a single essential amino acid causes a decrease in the synthesis of essentially all cellular proteins through an inhibition of the initiation phase of mRNA translation. However, the synthesis of all proteins is not repressed equally. Specific subsets of proteins, in particular those encoded by mRNAs containing a 5¹-terminal oligopyrimidine (TOP) motif, are affected to a much greater extent compared to most proteins. The specific decrease in TOP mRNA translation is a result of an inhibition of the ribosomal protein S6 kinase, S6K1, and a concomitant decline in S6 phosphorylation. Interestingly, many TOP mRNAs encode proteins involved in mRNA translation, such as elongation factors eEF1A and eEF2, as well as the ribosomal proteins. Thus, deprivation of essential amino acids not only directly and rapidly represses global mRNA translation, but also potentially results in a reduction in the capacity to synthesize protein.
 
 

Cellular control of protein degradation

Didier Attaix

Human Nutrition Research Center of Clermont-Ferrand and INRA, 63122 Ceyrat, FRANCE

A few years ago protein degradation was considered to be a global, non-selective and poorly regulated metabolic process that was mainly involved in housekeeping functions. This area of research has developed exponentially in the last decade, and it is now clear that many major biological functions are controlled by the breakdown of specific proteins. In this respect, the ubiquitin-proteasome-dependent pathway is the most elaborate protein-degradation machinery known. The formation of a polyubiquitin degradation signal is required for proteasome-dependent proteolysis. Several families of enzymes, which may comprise hundreds of members to achieve high selectivity, control this process. The substrates tagged by polyubiquitin chains are then recognized by the 26S proteasome and degraded into peptides. However, the 26S proteasome also recognizes and degrades some non-ubiquitinated proteins. Indeed, several ubiquitin- and/or proteasome-dependent systems degrade specific classes of substrates and single proteins by alternative mechanisms and are presumably interconnected. They may also interfere or cooperate with other proteolytic pathways.
 
 
 
 

Stress and Muscle Cachexia

Per-Olof Hasselgren

Department of Surgery, University of Cincinnati, Cincinnati, OH

One of the metabolic hallmarks of sepsis and severe injury is a catabolic response in skeletal muscle. Muscle cachexia in these conditions is mainly caused by increased protein breakdown, although inhibited protein synthesis contributes to the negative nitrogen balance in skeletal muscle. Muscle protein breakdown during sepsis and following severe injury mainly reflects degradation of the myofibrillar proteins actin and myosin. There is evidence that a calcium-calpain-dependent release of the myofilaments from the sarcomere provides substrates for the ubiquitin-proteasome proteolytic pathway. Proteins degraded by this pathway are ubiquitinated and subsequently degraded by the 26S proteasome. Research in our laboratory has provided evidence that the gene expression of calpains as well as various components of the ubiquitin proteasome pathway is upregulated in skeletal muscle during sepsis and following severe injury. In addition, proteasome inhibitors block the increase in muscle protein breakdown seen in these conditions. Muscle cachexia in patients with stress has important clinical implications because it can prevent or delay ambulation, increasing the risk for thromboembolic complications and prolonging rehabilitation. In addition, when respiratory muscles are affected, there is an increased risk for pulmonary complications and a need for prolonged ventilary support.
 
 
 

Developmental Regulation of Protein Metabolism

Teresa A. Davis

USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX

Growth and development are characterized by high rates of protein turnover that support rapid rates of protein accretion. The rate of protein deposition varies among tissues, with the growth rate of the skeletal musculature being amongst the highest. The efficiency with which dietary amino acids are utilized for protein deposition is high in neonates and decreases as the animal matures. This high efficiency is likely due to the enhanced stimulation of protein synthesis after feeding. The rise in protein synthesis in response to feeding and its developmental decline are more pronounced in skeletal muscle than for other tissues. In the neonatal pig, the postprandial rises in insulin and amino acids independently stimulate protein synthesis in skeletal muscle, whereas amino acids are the principal anabolic stimulus for liver. These developmental changes in protein synthesis are regulated by alterations in the expression and activity of components of the signaling pathway that controls the initiation of translation.
 
 

Muscle Wasting and Protein Metabolism

Carmen Castaneda Sceppa

Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University

Accelerated muscle proteolysis is the primary cause of muscle wasting in many catabolic diseases such as diabetes mellitus, renal and liver failure, HIV infection and AIDS, and cancer. In individuals with catabolic diseases, as it is the case of fasting states (anorexia and starvation), protein breakdown increases while protein synthesis declines resulting in negative muscle protein balance. The pathway responsible for accelerated proteolysis in catabolic conditions is the ubiquitin-proteosome dependent system. Muscle proteolysis increases under conditions of acidosis, up-regulation of branched-chain ketoacid dehydrogenase, the presence of catabolic hormones (glucocorticoids, thyrotoxic states), insulin resistance, and multiple cytokines (interlukin-1 and 6 and tumor necrosis factor). In contrast, factors that suppress muscle proteolysis and wasting leading to a state of adaptation include dietary protein deficiency with adequate energy intake, use of anabolic agents, and resistance exercise training. The understanding of the biochemical adaptation that reduce protein degradation and improve nitrogen balance are important for the development of effective therapies to combat muscle wasting and improve protein homeostasis with catabolic illnesses.
 
 

Exercise and Protein Metabolism

Robert R. Wolfe

University of Texas Medical Branch and Shriners Burns Hospital, Galveston, Texas

Resistance exercise training produces an anabolic effect on muscle, yet during exercise muscle protein synthesis is not stimulated, and muscle protein breakdown may be accelerated. The anabolic response begins after the exercise is completed. Muscle protein synthesis is elevated by about one hour after exercise, and remains elevated for as long as 48 hours. A simultaneous increase in muscle protein breakdown blunts the effect of the stimulation of synthesis on the net protein balance. Net muscle protein balance is improved after exercise, but remains negative unless nutrients are ingested. Thus, the "anabolic" response to resistance exercise occurs in the fed state, where ingested amino acids are incorporated into muscle protein to a greater extent than when ingested at rest.
 
 

Hormonal Regulation of Regional and Tissue Protein Turnover

Sreekumaran Nair

Endocrinology Unit, Mayo Clinic, Rochester, MN

Hormones are major regulators of protein turnover in humans. Whole body protein balance and tissue concetrations of specific proteins are determined by the balance between synthesis and degradation of proteins. Most of the hormonal actions are tissue and protein specific and the same hormone may inhibit synthesis of one protein but directly or indirectly stimulate synthesis of another protein. Hormonal effects are targeted at different levels of regulation of protein synthesis and degradation. Examples of hormonal imbalance resulting in profound changes in protein turnover is evident in type I diabetes. Insulin deficiency results in elevated glucagon and growth hormone levels in human. Insulin deficiency has been shown to result in profound muscle wasting by a net increase in muscle protein breakdown. High glucagon causes increased metabolic rate and accelerated leucine oxidation thus contributing to the catabolic state in diabetes. Other catabolic hormones such as cortisol also may contribute to catabolism. Insulin also is a key hormone involved in regulating the trafficking of amino acids across organs especially making amino acids available for synthesizing essential proteins in between meals. Recent interest has focused on insulin specific effects on certain proteins with specific functions such as mitochondrial proteins. Hormones also act in conjunction with substrates which modulates hormonal effect on protein turnover.
 
 

Nutritional Regulation of Protein Metabolism

Peter J. Garlick

Department of Surgery, State University of New York at Stony Brook, Stony Brook, NY

Protein homeostasis depends on the balance between protein synthesis and protein degradation. In muscle of growing animals, feeding is accompanied by an increase in protein synthesis, resulting in net protein deposition. This has been shown to depend on amino acid supply and insulin secretion. In contrast, in the liver, protein deposition after feeding results mainly from an inhibition of protein degradation. At the whole body level, increasing nutrient intake in human preterm neonates has been shown to be associated with increased protein deposition, resulting from enhanced protein synthesis. In healthy adults there is no growth, but there is a need to retain protein after meals to counter the protein loss that occurs postabsorptively. The adult rat shows little stimulation of muscle protein synthesis by food intake or insulin infusion, whereas in human muscle the responses to nutrients or insulin remain controversial. Pathological conditions such as trauma and infection are characterized by muscle protein loss and a decrease in muscle protein synthesis, and much effort has been spent on strategies for reversing muscle wasting by nutritional and pharmacological means. However, nutritional support, even when supplemented with branched chain amino acids or glutamine, have not yet been shown to be effective.
 

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