Effect of Insulin on Amino Acid Uptake and Protein Turnover in Skeletal Muscle From Septic Rats

Hasselgren, Per-Olof; Warner, Brad W.; James, J. Howard; Takehara, Hiroo; Fischer, Josef E.

doi:10.1001/archsurg.1987.01400140110015

Cited by 57 publications

(33 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides suppressing protein synthesis, our findings show that a reduced PI3K activity contributes to muscle atrophy via coordinated regulation of apoptotic and Ub-P'some systems, ultimately leading to protein degradation. It is tempting to speculate that the identified pathways account for the excessive muscle protein loss that occurs in conditions associated with insulin resistance, including metabolic acidosis, uremia, and conditions that increase glucocorticoids (11,16,27,(35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Muscle Protein Degradation

Lee

Dai

et al. 2004

Journal of the American Society of Nephrology

306

263

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Regulation of Muscle Protein Degradation

Lee

Dai

et al. 2004

Journal of the American Society of Nephrology

306

263

View full text Add to dashboard Cite

“…Conditions such as chronic uremia or sepsis that cause muscle atrophy are frequently characterized by insulin resistance (22,23), and there is decreased activity of PI3K in models of insulin resistance (24). Since PI3K is an antiapoptotic mediator, it could regulate the activity of caspase-3 (41,42).…”

Section: Figurementioning

confidence: 99%

Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions

Du¹,

Wang²,

Miereles³

et al. 2004

J. Clin. Invest.

613

303

View full text Add to dashboard Cite

With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P'some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P'some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P'some system. Therapeutic strategies could be designed to prevent these events.

show abstract

“…Total protein degradation was estimated simultaneously with the rate of protein synthesis as the sum of the accumulation of tyrosine in the incubation buffer over a 1-h period plus the amount of tyrosine equivalents incorporated into protein via protein synthesis during the same time interval as described previously (Tischler & Fagan 1983, Hasselgren et al 1987, 1989, Dardevet et al 1994, 1998, Voisin et al 1996, Vary et al 1998). Because tyrosine is neither synthesized nor metabolized by muscle, except for use by protein synthesis, the release of tyrosine from muscle into the incubation medium reflects net protein balance.…”

Section: Protein Degradationmentioning

confidence: 99%

“…Both these metabolic processes show a resistance to the anabolic actions of insulin during sepsis. With respect to protein metabolism, proteolysis in skeletal muscle consistently shows a relative resistance to inhibition by insulin during the period immediately after a trauma (Tischler & Fagan 1983) or during acute (16 h) peritonitis (Hasselgren et al 1987(Hasselgren et al , 1989. In contrast, the ability of insulin to enhance protein synthesis is variable in skeletal muscle during sepsis.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the ability of insulin to enhance protein synthesis is variable in skeletal muscle during sepsis. During the period immediately after infection (up to 48 h), insulin stimulates protein synthesis (Tischler & Fagan 1983, Hasselgren et al 1987, 1989, However, during chronic (5-day) intra-abdominal sepsis, insulin was without effect in augmenting skeletal muscle protein synthesis ( Jurasinski et al 1995a).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pentoxifylline improves insulin action limiting skeletal muscle catabolism after infection

Vary¹,

Dardevet²,

Grizard³

et al. 1999

Journal of Endocrinology

View full text Add to dashboard Cite

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.

show abstract

Effect of Insulin on Amino Acid Uptake and Protein Turnover in Skeletal Muscle From Septic Rats

Cited by 57 publications

References 38 publications

Regulation of Muscle Protein Degradation

Regulation of Muscle Protein Degradation

Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions

Pentoxifylline improves insulin action limiting skeletal muscle catabolism after infection

Contact Info

Product

Resources

About