Is extracellular matrix remodeling in skeletal muscle a metabolic memory component in the development of hyperglycemia?
Invited conference paper presented and published in conference proceedings
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AbstractIntroduction
Metabolic memory is regarded as the legacy of pre-exposed stimulations [1], attributed to the duration and intensity of associated protein, RNA expression, chromatin modification, etc. In diabetes, metabolic memory might contribute to the significant increase in diabetic complication risks in long-term follow-up [2]. However, the involvement of metabolic memory in disease development in the early phase is unclear. Given that insulin resistance of skeletal muscle is an early change in diabetes development and its implication in disease progression [3], we asked if short-term high-fat diet (HFD) treatment could induce persistent skeletal muscle changes which manifested as metabolic memory and affect the development of hyperglycemia.
Experiments
Twelve-week-old male C57BL/6J mice were subjected to different regimes of 16 weeks HFD treatment, including HFD 5 weeks(W) – control diet (CD) 6W – HFD 5W vs. CD 5W – CD 6W – CD 5W). Six mice per group were sacrificed at each stage to collect extensor digitorum longus (EDL) and gastrocnemius (GA) muscles to measure muscle passive and active properties and other molecular parameters to characterize changes related to metabolic memory. Bulk RNA sequencing was used to identify the key differential expressing genes (DEGs) during the treatment. Moreover, in vitro functional experiments were applied to verify our findings. ANOVA statistical analysis was used in this study.
Results and Discussion
The RNA sequencing results showed that, in skeletal muscle, two clusters of DEGs exhibited metabolic memory-like expression pattern, which is enriched with ECM remodeling-related genes and possibly activated the AGE-RAGE signaling pathway. In vivo experiments showed that intramuscular hydroxyproline and AGE, muscle stiffness, and viscoelasticity were persistently upregulated. Because of the high AGE content and muscle stiffness, a culture model with different substrate stiffness was used to test extracellular stiffness's effect on myoblast cells' insulin resistance. Cells in a stiffer environment had lower pAkt, Akt protein expression, and insulin-induced glucose uptake even though the high-glucose environment was removed.
Our findings indicate that AGE content and muscle stiffness at the early phase of HFD treatment might represent a new phenotypic change of metabolic memory, which affect the onset of hyperglycemia and provide a new avenue to develop new approaches to reverse the disease progression.
Metabolic memory is regarded as the legacy of pre-exposed stimulations [1], attributed to the duration and intensity of associated protein, RNA expression, chromatin modification, etc. In diabetes, metabolic memory might contribute to the significant increase in diabetic complication risks in long-term follow-up [2]. However, the involvement of metabolic memory in disease development in the early phase is unclear. Given that insulin resistance of skeletal muscle is an early change in diabetes development and its implication in disease progression [3], we asked if short-term high-fat diet (HFD) treatment could induce persistent skeletal muscle changes which manifested as metabolic memory and affect the development of hyperglycemia.
Experiments
Twelve-week-old male C57BL/6J mice were subjected to different regimes of 16 weeks HFD treatment, including HFD 5 weeks(W) – control diet (CD) 6W – HFD 5W vs. CD 5W – CD 6W – CD 5W). Six mice per group were sacrificed at each stage to collect extensor digitorum longus (EDL) and gastrocnemius (GA) muscles to measure muscle passive and active properties and other molecular parameters to characterize changes related to metabolic memory. Bulk RNA sequencing was used to identify the key differential expressing genes (DEGs) during the treatment. Moreover, in vitro functional experiments were applied to verify our findings. ANOVA statistical analysis was used in this study.
Results and Discussion
The RNA sequencing results showed that, in skeletal muscle, two clusters of DEGs exhibited metabolic memory-like expression pattern, which is enriched with ECM remodeling-related genes and possibly activated the AGE-RAGE signaling pathway. In vivo experiments showed that intramuscular hydroxyproline and AGE, muscle stiffness, and viscoelasticity were persistently upregulated. Because of the high AGE content and muscle stiffness, a culture model with different substrate stiffness was used to test extracellular stiffness's effect on myoblast cells' insulin resistance. Cells in a stiffer environment had lower pAkt, Akt protein expression, and insulin-induced glucose uptake even though the high-glucose environment was removed.
Our findings indicate that AGE content and muscle stiffness at the early phase of HFD treatment might represent a new phenotypic change of metabolic memory, which affect the onset of hyperglycemia and provide a new avenue to develop new approaches to reverse the disease progression.
All Author(s) ListHSIAO Wei Ting, LEE Chien-Wei, LEE Wayne Yuk-wai
Name of ConferenceTERMIS-AP Virtual Student Paper Contest
Start Date of Conference17/12/2022
End Date of Conference18/12/2022
Place of ConferenceHong Kong
Country/Region of ConferenceHong Kong
Year2022
Month12
LanguagesEnglish-United Kingdom
