Mechanism of attenuation of skeletal muscle atrophy by zinc-α2-glycoprotein

Steven Russell, Michael Tisdale

Research output: Contribution to journalArticle

Abstract

The mechanism by which the adipokine zinc-a2-glycoprotein (ZAG) increases the mass of gastrocnemius, but not soleus muscle of diabetic mice, has been evaluated both in vivo and in vitro. There was an increased phosphorylation of both double-stranded RNA-dependent protein kinase and its substrate, eukaryotic initiation factor-2a, which was attenuated by about two-thirds in gastrocnemius but not soleus muscle of ob/ob mice treated with ZAG (50 µg, iv daily) for 5 d. ZAG also reduced the expression of the phospho forms of p38MAPK and phospholipase A2, as well as expression of the ubiquitin ligases (E3) muscle atrophy F-box/atrogin-1 and muscle RING finger protein, and the increased activity of both caspase-3 and casapse-8 to values found in nonobese controls. ZAG also increased the levels of phospho serine-threonine kinase and mammalian target of rapamycin in gastrocnemius muscle and reduced the phosphorylation of insulin receptor substrate-1 (Ser307) associated with insulin resistance. Similar changes were seen with ZAG when murine myotubes were incubated with high glucose concentrations (10 and 25 mm), showing that the effect of ZAG was direct. ZAG produced an increase in cAMP in murine myotubes, and the effects of ZAG on protein synthesis and degradation in vitro could be replicated by dibutyryl cAMP. ZAG increased cAMP levels of gastrocnemius but not soleus muscle. These results suggest that protein accretion in skeletal muscle in response to ZAG may be due to changes in intracellular cAMP and also that ZAG may have a therapeutic application in the treatment of muscle wasting conditions.
LanguageEnglish
Pages4696-4704
Number of pages9
JournalEndocrinology
Volume151
Issue number10
DOIs
Publication statusPublished - Oct 2010

Fingerprint

Muscular Atrophy
Zinc
Glycoproteins
Skeletal Muscle
Skeletal Muscle Fibers
Phosphorylation
eIF-2 Kinase
Eukaryotic Initiation Factors
Insulin Receptor Substrate Proteins
Muscles
Adipokines
Ubiquitin-Protein Ligases
Double-Stranded RNA
Protein-Serine-Threonine Kinases
Phospholipases A2
Sirolimus
Caspase 3
Proteolysis
Insulin Resistance
Proteins

Keywords

  • animals
  • cultured cells
  • cytoprotection
  • experimental diabetes mellitus
  • type 2 diabetes mellitus
  • preclinical drug evaluation
  • humans
  • mice
  • obese mice
  • skeletal muscle fibers
  • skeletal muscle
  • muscular atrophy
  • obesity
  • seminal plasma proteins
  • p38 mitogen-activated protein kinases

Cite this

Russell, Steven ; Tisdale, Michael. / Mechanism of attenuation of skeletal muscle atrophy by zinc-α2-glycoprotein. In: Endocrinology. 2010 ; Vol. 151, No. 10. pp. 4696-4704.
@article{17962eaefabb4246b76810c5d31773d9,
title = "Mechanism of attenuation of skeletal muscle atrophy by zinc-α2-glycoprotein",
abstract = "The mechanism by which the adipokine zinc-a2-glycoprotein (ZAG) increases the mass of gastrocnemius, but not soleus muscle of diabetic mice, has been evaluated both in vivo and in vitro. There was an increased phosphorylation of both double-stranded RNA-dependent protein kinase and its substrate, eukaryotic initiation factor-2a, which was attenuated by about two-thirds in gastrocnemius but not soleus muscle of ob/ob mice treated with ZAG (50 µg, iv daily) for 5 d. ZAG also reduced the expression of the phospho forms of p38MAPK and phospholipase A2, as well as expression of the ubiquitin ligases (E3) muscle atrophy F-box/atrogin-1 and muscle RING finger protein, and the increased activity of both caspase-3 and casapse-8 to values found in nonobese controls. ZAG also increased the levels of phospho serine-threonine kinase and mammalian target of rapamycin in gastrocnemius muscle and reduced the phosphorylation of insulin receptor substrate-1 (Ser307) associated with insulin resistance. Similar changes were seen with ZAG when murine myotubes were incubated with high glucose concentrations (10 and 25 mm), showing that the effect of ZAG was direct. ZAG produced an increase in cAMP in murine myotubes, and the effects of ZAG on protein synthesis and degradation in vitro could be replicated by dibutyryl cAMP. ZAG increased cAMP levels of gastrocnemius but not soleus muscle. These results suggest that protein accretion in skeletal muscle in response to ZAG may be due to changes in intracellular cAMP and also that ZAG may have a therapeutic application in the treatment of muscle wasting conditions.",
keywords = "animals, cultured cells, cytoprotection, experimental diabetes mellitus, type 2 diabetes mellitus, preclinical drug evaluation, humans, mice, obese mice, skeletal muscle fibers, skeletal muscle, muscular atrophy, obesity, seminal plasma proteins, p38 mitogen-activated protein kinases",
author = "Steven Russell and Michael Tisdale",
year = "2010",
month = "10",
doi = "10.1210/en.2010-0532",
language = "English",
volume = "151",
pages = "4696--4704",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "10",

}

Mechanism of attenuation of skeletal muscle atrophy by zinc-α2-glycoprotein. / Russell, Steven; Tisdale, Michael.

In: Endocrinology, Vol. 151, No. 10, 10.2010, p. 4696-4704.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mechanism of attenuation of skeletal muscle atrophy by zinc-α2-glycoprotein

AU - Russell, Steven

AU - Tisdale, Michael

PY - 2010/10

Y1 - 2010/10

N2 - The mechanism by which the adipokine zinc-a2-glycoprotein (ZAG) increases the mass of gastrocnemius, but not soleus muscle of diabetic mice, has been evaluated both in vivo and in vitro. There was an increased phosphorylation of both double-stranded RNA-dependent protein kinase and its substrate, eukaryotic initiation factor-2a, which was attenuated by about two-thirds in gastrocnemius but not soleus muscle of ob/ob mice treated with ZAG (50 µg, iv daily) for 5 d. ZAG also reduced the expression of the phospho forms of p38MAPK and phospholipase A2, as well as expression of the ubiquitin ligases (E3) muscle atrophy F-box/atrogin-1 and muscle RING finger protein, and the increased activity of both caspase-3 and casapse-8 to values found in nonobese controls. ZAG also increased the levels of phospho serine-threonine kinase and mammalian target of rapamycin in gastrocnemius muscle and reduced the phosphorylation of insulin receptor substrate-1 (Ser307) associated with insulin resistance. Similar changes were seen with ZAG when murine myotubes were incubated with high glucose concentrations (10 and 25 mm), showing that the effect of ZAG was direct. ZAG produced an increase in cAMP in murine myotubes, and the effects of ZAG on protein synthesis and degradation in vitro could be replicated by dibutyryl cAMP. ZAG increased cAMP levels of gastrocnemius but not soleus muscle. These results suggest that protein accretion in skeletal muscle in response to ZAG may be due to changes in intracellular cAMP and also that ZAG may have a therapeutic application in the treatment of muscle wasting conditions.

AB - The mechanism by which the adipokine zinc-a2-glycoprotein (ZAG) increases the mass of gastrocnemius, but not soleus muscle of diabetic mice, has been evaluated both in vivo and in vitro. There was an increased phosphorylation of both double-stranded RNA-dependent protein kinase and its substrate, eukaryotic initiation factor-2a, which was attenuated by about two-thirds in gastrocnemius but not soleus muscle of ob/ob mice treated with ZAG (50 µg, iv daily) for 5 d. ZAG also reduced the expression of the phospho forms of p38MAPK and phospholipase A2, as well as expression of the ubiquitin ligases (E3) muscle atrophy F-box/atrogin-1 and muscle RING finger protein, and the increased activity of both caspase-3 and casapse-8 to values found in nonobese controls. ZAG also increased the levels of phospho serine-threonine kinase and mammalian target of rapamycin in gastrocnemius muscle and reduced the phosphorylation of insulin receptor substrate-1 (Ser307) associated with insulin resistance. Similar changes were seen with ZAG when murine myotubes were incubated with high glucose concentrations (10 and 25 mm), showing that the effect of ZAG was direct. ZAG produced an increase in cAMP in murine myotubes, and the effects of ZAG on protein synthesis and degradation in vitro could be replicated by dibutyryl cAMP. ZAG increased cAMP levels of gastrocnemius but not soleus muscle. These results suggest that protein accretion in skeletal muscle in response to ZAG may be due to changes in intracellular cAMP and also that ZAG may have a therapeutic application in the treatment of muscle wasting conditions.

KW - animals

KW - cultured cells

KW - cytoprotection

KW - experimental diabetes mellitus

KW - type 2 diabetes mellitus

KW - preclinical drug evaluation

KW - humans

KW - mice

KW - obese mice

KW - skeletal muscle fibers

KW - skeletal muscle

KW - muscular atrophy

KW - obesity

KW - seminal plasma proteins

KW - p38 mitogen-activated protein kinases

UR - http://www.scopus.com/inward/record.url?scp=77957262213&partnerID=8YFLogxK

U2 - 10.1210/en.2010-0532

DO - 10.1210/en.2010-0532

M3 - Article

VL - 151

SP - 4696

EP - 4704

JO - Endocrinology

T2 - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 10

ER -