Streptozotocin induces G2 arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada Submitted 19 June 2006 ; accepted in final form 1 November 2006 Streptozotocin (STZ) is used extensively to induce pancreatic -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 µm 2 , respectively; P < 0.05) and insulin treatment did not rescue this defect (STZ-INS: 1,476 ± 143 µm 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 (0.25–3.0mg/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 -cell specific and reveal that STZ should not be used for studies examining diabetic myopathy. satellite cell; diabetes; diabetic model; type 1 diabetes mellitus; cell cycle; proliferation; hypertrophy Address for reprint requests and other correspondence: T. J. Hawke, School of Kinesiology and Health Science, York Univ., 4700 Keele St., Toronto, Ontario, Canada, M3J 1P3 (e-mail: thawke{at}yorku.ca )