Keywords

apoptosis, atrophy, myopathy, sarcopenia, diabetes, sterile inflammation, necroptosis, diabetic cardiomyopathy, MSC, exosome therapy

Abstract

Hyperglycemia and dyslipidemia are common comorbidities that often coincide and have a significant impact on the severity of diabetes. This current study investigates the pathology and mechanism behind skeletal muscle cachexia and cardiac dysfunction in diabetic dyslipidemia. Stem cells continue to be critical as a regenerative strategy to restore damaged tissue, however, several drawbacks have been observed with use of stem cells including thrombogenesis, low survival, and tumorigenicity. Therefore, we isolated exosomes from stem cells and assessed their ability to attenuate diabetes-induced sarcopenia and cardiomyopathy. Exosomes are nanosized particles released by cells, containing proteins and nucleic acids that allow it to exhibit similar properties to the cell type of origin. To model diabetic dyslipidemia, we utilized ApoE knockout mice (10±2 weeks) and divided them into 4 groups consisting of control (saline intraperitoneal (IP) injection), diabetic (STZ IP injection), treatment group administered intravenous (IV) exosomes derived from miR-1 ES-Exos (microRNA-1 enriched Embryonic Stem Cells) or MSC-Exos (Mesenchymal Stem Cells), and negative control treatment MEF-Exos (Mouse Embryonic Fibroblasts). Heart and soleus tissue samples were analyzed for inflammation, inflammatory cell death expression, and adverse tissue remodeling using histology, immunohistochemistry, western blotting, RT-PCR, cytokine, and luciferase-based arrays. In summary we found diabetic dyslipidemic mice acquire cardiac and skeletal muscle dysfunction. Administration of miR-1 ES-Exos and MSC-Exos significantly mitigated inflammation and cell death marker expression, resulting in improved cardiac and skeletal muscle function. In conclusion our data shows that miR-1 ES-Exos and MSC-Exos are effective therapeutic agents in attenuating diabetes-induced sarcopenia and cardiomyopathy.

Completion Date

2024

Semester

Spring

Committee Chair

Singla, Dinender

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Biomedical Science

Degree Program

Biomedical Sciences

Format

application/pdf

Language

English

Rights

In copyright

Release Date

May 2025

Length of Campus-only Access

1 year

Access Status

Doctoral Dissertation (Campus-only Access)

Campus Location

Orlando (Main) Campus

Accessibility Status

Meets minimum standards for ETDs/HUTs

Restricted to the UCF community until May 2025; it will then be open access.

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