Exploring the Mechanism of Skeletal Muscle in a Tacrolimus-Induced Posttransplantation Diabetes Mellitus Model on Gene Expression Profiles

Abstract

Objective. Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle. Methods. We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus. Results. Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin. Conclusions. This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.

Loss of NOR‐1 represses muscle metabolism through mTORC1‐mediated signaling and mitochondrial gene expression in C2C12 myotubes

“…Tacrolimus is a calcineurin inhibitor that is associated with an increased incidence of postorgan transplant diabetes mellitus and skeletal muscle dysfunction. 52 In skeletal muscle cells, inhibition of calcineurin prevents calcium-mediated induction of NOR-1. 27 These data open up the possibility that NOR-1 expression may be altered in skeletal muscle after tacrolimus exposure.…”

“…Interestingly, the drug tacrolimus was predicted as being overly abundant, based on DEGs in our RNA‐Seq analysis. Tacrolimus is a calcineurin inhibitor that is associated with an increased incidence of postorgan transplant diabetes mellitus and skeletal muscle dysfunction 52 . In skeletal muscle cells, inhibition of calcineurin prevents calcium‐mediated induction of NOR‐1 27 .…”

Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity

“…TAC induced weight loss was common in the diabetic model, and vancomycin did not reverse it here. 42 , 43 No discernible differences in fasting glucose levels were observed among the three groups ( Figure 1b ). A set of tests was performed to assess the effects of TAC on glucose homeostasis and insulin sensitivity.…”

Comparison of Muscle Regeneration after BMSC-Conditioned Medium, Syngeneic, or Allogeneic BMSC Injection

“…Therefore, the presence of such cells in damaged muscle may lead to prolonged inflammation, which could eventually lead to progressive muscle weakness, muscle atrophy, and damage to neighboring structures, such as the vasculature [ 15 ]. Graft rejection could be circumvented with the application of immunosuppression, but known immunosuppressive agents can also affect skeletal muscles by blocking myoblast fusion or causing muscle atrophy [ 16 ] (Świerczek-Lasek et al, in preparation).…”