Streptozotocin induces G2 arrest in skeletal muscle myoblasts and impairs muscle growth in vivo.
Streptozotocin (STZ) is used extensively to induce pancreatic beta-cell death and ultimately diabetes mellitus in animal models. However, the direct effects of STZ on muscle are largely unknown. To delineate the effects of STZ from the effects of hypoinsulinemia/hyperglycemia, we injected young rats with 1) saline (control), 2) STZ (120 mg/kg) or 3) STZ and insulin (STZ-INS; to maintain euglycemia). STZ rats demonstrated significantly elevated blood glucose throughout the 48-h protocol, while control and STZ-INS rats were euglycemic. Body mass increased in control (13 +/- 4 g), decreased by 19 +/- 2 g in STZ and remained unchanged in STZ-INS rats (-0.3 +/- 2 g). Cross-sectional areas of gastrocnemius muscle fibers were smaller in STZ vs. control (1,480 +/- 149 vs. 1,870 +/- 40 microm(2), respectively; P < 0.05) and insulin treatment did not rescue this defect (STZ-INS: 1,476 +/- 143 microm(2)). Western blot analysis revealed a detectable increase in ubiquitinated proteins in the STZ skeletal muscles compared with control and STZ-INS. To further define the effects of STZ on skeletal muscle, independent of hyperglycemia, myoblasts were exposed to varying doses of STZ (0.25-3.0 mg/ml) in vitro. Both acute and chronic exposures of STZ significantly impaired proliferative capacity in a dose-dependent manner. Within STZ-treated myoblasts, increased reactive oxygen species was associated with significant G(2)/M phase cell-cycle arrest. Taken together, our findings show that the effects of STZ are not beta-cell specific and reveal that STZ should not be used for studies examining diabetic myopathy.
Johnston
Adam P W
AP
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada M3J 1P3.
Campbell
Jonathan E
JE
Found
Jeremy G
JG
Riddell
Michael C
MC
Hawke
Thomas J
TJ
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development*; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000008:administration & dosage*
D013311:Streptozocin