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Autophagy in muscle of glucose-infusion hyperglycemia rats and streptozotocin-induced hyperglycemia rats via selective activation of m-TOR or FoxO3.

ABSTRACT: Autophagy is a conserved process in eukaryotes required for metabolism and is involved in diverse diseases. To investigate autophagy in skeletal muscle under hyperglycemia status, we established two hyperglycemia-rat models that differ in their circulating insulin levels, by glucose infusion and singe high-dose streptozotocin injection. We then detected expression of autophagy related genes with real-time PCR and western blot. We found that under hyperglycemia status induced by glucose-infusion, autophagy was inhibited in rat skeletal muscle, whereas under streptozotocin-induced hyperglycemia status autophagy was enhanced. Meanwhile, hyperglycemic gastrocnemius muscle was more prone to autophagy than soleus muscle. Furthermore, inhibition of autophagy in skeletal muscle in glucose-infusion hyperglycemia rats was mediated by the m-TOR pathway while m-TOR and FoxO3 both contributed to enhancement of autophagy in gastrocnemius muscle in streptozotocin-induced hyperglycemia rats. These data shows that insulin plays a relatively more important role than hyperglycemia in regulating autophagy in hyperglycemia rat muscle through selectively activating the m-TOR or FoxO3 pathway in a fiber-selective manner.

SUBMITTER: Lv P

PROVIDER: S-EPMC3911944 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Autophagy in muscle of glucose-infusion hyperglycemia rats and streptozotocin-induced hyperglycemia rats via selective activation of m-TOR or FoxO3.

Lv Pengfei P Huang Jian J Yang Jian J Deng Yujie Y Xu Jun J Zhang Xiaoyan X Li Wenyi W Zhang Hongli H Yang Ying Y

PloS one 20140203 2

Autophagy is a conserved process in eukaryotes required for metabolism and is involved in diverse diseases. To investigate autophagy in skeletal muscle under hyperglycemia status, we established two hyperglycemia-rat models that differ in their circulating insulin levels, by glucose infusion and singe high-dose streptozotocin injection. We then detected expression of autophagy related genes with real-time PCR and western blot. We found that under hyperglycemia status induced by glucose-infusion, ...[more]

PMID: 24498304

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Project description:Introduction: Chemicals, such as MNU (N-methyl-N-nitrosourea) and NaIO3 (sodium iodate), are widely used to induce retinal degeneration in rodents. Streptozotocin (STZ) is an analog of N-acetyl glucosamine in which an MNU moiety is linked to a hexose and has a special toxic effect on insulin-producing pancreatic β-cells. It is commonly used to induce hyperglycemia to model diabetes. While intracerebroventricular injection of STZ can produce Alzheimer's disease independent of hyperglycemia, most retinal studies using STZ focus on the effects of hyperglycemia on the retina, but whether STZ has any impact on retinal cells independent of hyperglycemia is unknown. We aimed to investigate the role of cytotoxicity of STZ in rat retina. Methods: Intravitreal or subcutaneous injection of STZ was performed on newborn rats. Electroretinogram (ERG) and H&E staining investigated retinal function and morphological changes. Retinal cell types, cell death, proliferation, inflammation, and angiogenesis were studied by immunostaining. RNA sequencing was performed to examine the transcriptome changes of retinal cells after intravitreal injection of STZ. Results: Intravitreal (5 μg or 10 μg) or subcutaneous (30 mg/kg) injection of STZ at the early stage of newborn rats couldn't induce hyperglycemia but caused NSIR (Neonatal STZ-induced retinopathy), including reduced ERG amplitudes, retinal rosettes and apoptosis, cell cycle arrest, microglial activation, and delayed retinal angiogenesis. STZ did not affect the early-born retinal cell types but significantly reduced the late-born ones. Short-term and long-term hyperglycemia had no significant effects on the NSIR phenotypes. RNA sequencing revealed that STZ induces oxidative stress and activates the p53 pathway of retinal cells. Locally or systemically, STZ injection after P8 couldn't induce SINR when all retinal progenitors exit the cell cycle. Conclusion: NSIR in rats is independent of hyperglycemia but due to STZ's direct cytotoxic effects on retinal progenitor cells. NSIR is a typical reaction to STZ-induced retinal oxidative stress and DNA damage. This significant finding suggests that NSIR may be a valuable model for studying retinal progenitor DNA damage-related diseases, potentially leading to new insights and treatments.

Project description:Diabetes mellitus (DM) poses a significant global health burden, with hyperglycemia being a primary contributor to complications and high morbidity associated with this disorder. Existing glucose management strategies have shown suboptimal effectiveness, necessitating alternative approaches. In this study, we explored the role of high mobility group box 1 (HMGB1) in hyperglycemia, a protein implicated in initiating inflammation and strongly correlated with DM onset and progression. We hypothesized that HMGB1 knockdown will mitigate hyperglycemia severity and enhance glucose tolerance. To test this hypothesis, we utilized a novel inducible HMGB1 knockout (iHMGB1 KO) mouse model exhibiting systemic HMGB1 knockdown. Hyperglycemic phenotype was induced using low dose streptozotocin (STZ) injections, followed by longitudinal glucose measurements and oral glucose tolerance tests to evaluate the effect of HMGB1 knockdown on glucose metabolism. Our findings showed a substantial reduction in glucose levels and enhanced glucose tolerance in HMGB1 knockdown mice. Additionally, we performed RNA sequencing analyses, which identified potential alternations in genes and molecular pathways within the liver and skeletal muscle tissue that may account for the in vivo phenotypic changes observed in hyperglycemic mice following HMGB1 knockdown. In conclusion, our present study delivers the first direct evidence of a causal relationship between systemic HMGB1 knockdown and hyperglycemia in vivo, an association that had remained unexamined prior to this research. This discovery positions HMGB1 knockdown as a potentially efficacious therapeutic target for addressing hyperglycemia and, by extension, the DM epidemic. Furthermore, we have revealed potential underlying mechanisms, establishing the essential groundwork for subsequent in-depth mechanistic investigations focused on further elucidating and harnessing the promising therapeutic potential of HMGB1 in DM management.

Project description:BackgroundC-peptide therapy exerts several positive actions on nerves, vasculature, smooth muscle relaxation, kidney function and bone. To date, the role of C-peptide in preventing type 1 diabetes-related muscle atrophy has not been investigated. Our aim was to evaluate if C-peptide infusion prevents muscle wasting in diabetic rats.MethodsTwenty-three male Wistar rats were randomly divided into three groups: normal control group, diabetic group and diabetic group plus C-peptide. Diabetes was induced by streptozotocin injection, and C-peptide was administered subcutaneously for 6 weeks. The blood samples were obtained at baseline, before streptozotocin injection and at the end of the study to assess C-peptide, ubiquitin and other laboratory parameters. We also tested the ability of C-peptide to regulate the skeletal muscle mass, the ubiquitin-proteasome system, the autophagy pathway as well as to improve muscle quality.ResultsC-peptide administration reversed hyperglycaemia (P = 0.02) and hypertriglyceridaemia (P = 0.01) in diabetic plus C-peptide rats compared with diabetic control rats. The diabetic-control animals displayed a lower weight of the muscles in the lower limb considered individually than the control rats and the diabetic plus C-peptide rats (P = 0.03; P = 0.03; P = 0.04; P = 0.004, respectively). The diabetic-control rats presented a significantly higher serum concentration of ubiquitin compared with the diabetic plus C-peptide and the control animals (P = 0.02 and P = 0.01). In muscles of the lower limb, the pAmpk expression was higher in the diabetic plus C-peptide than the diabetic-control rats (in the gastrocnemius, P = 0.002; in the tibialis anterior P = 0.005). The protein expression of Atrogin-1 in gastrocnemius and tibialis was lower in the diabetic plus C-peptide than in diabetic-control rats (P = 0.02, P = 0.03). After 42 days, the cross-sectional area in the gastrocnemius of the diabetic plus C-peptide group had been reduced by 6.6% while the diabetic-control rats had a 39.5% reduction compared with the control animals (P = 0.02). The cross-sectional area of the tibialis and the extensor digitorum longus muscles was reduced, in the diabetic plus C-peptide rats, by 10% and 11%, respectively, while the diabetic-control group had a reduction of 65% and 45% compared with the control animals (both P < 0.0001). Similar results were obtained for the minimum Feret's diameter and perimeter.ConclusionsC-peptide administration in rats could protect skeletal muscle mass from atrophy induced by type 1 diabetes mellitus. Our findings could suggest that targeting the ubiquitin-proteasome system, Ampk and muscle-specific E3 ubiquitin ligases such as Atrogin-1 and Traf6 may be an effective strategy for molecular and clinical intervention in the muscle wasting pathological process in T1DM.

Dataset Information

Autophagy in muscle of glucose-infusion hyperglycemia rats and streptozotocin-induced hyperglycemia rats via selective activation of m-TOR or FoxO3.

Publications

Autophagy in muscle of glucose-infusion hyperglycemia rats and streptozotocin-induced hyperglycemia rats via selective activation of m-TOR or FoxO3.

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