Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice

Khin, Phyu Phyu; Hong, Yeonhee; Yeon, MyeongHoon; Lee, Dong Hoon; Lee, Jong Han; Jun, Hee-Sook

doi:10.18632/aging.203546

Cited by 15 publications

(13 citation statements)

References 41 publications

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“…Since aging causes fragmentation of mitochondria, a hallmark for this process is loss of Opa-1 and MICOS complex proteins. We hypothesized that aging would also lead to decreases in the associated MICOS complex proteins, confirming prior studies which have found Opa-1 loss across aging 19,23–25 . We found progressive loss of both Opa-1 and MICOS complex subunits, as measured by loss of transcripts for the proteins (SFigure 3A–D).…”

Section: Resultssupporting

confidence: 85%

3D Reconstruction of Murine Mitochondria Exhibits Changes in Structure Across Aging Linked to the MICOS Complex

Vue

Lopez

Neikirk

et al. 2022

Preprint

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Background: Skeletal muscle gradually loses mass, strength, endurance, and oxidative capacity during aging. Studies of bioenergetics and protein turnover show that mitochondria mediate this decline in function. Mitochondria are essential for the production of ATP, which occurs in the cristae, the folds of the inner mitochondrial membrane. While mitochondrial aging is associated with endoplasmic reticulum stress, fragmented mitochondria, and decreased mitochondrial capacity, the genes associated with morphological changes in mitochondria during aging are unknown. Further, we do not understand how 3D mitochondrial networks and the specialization of mitochondria alter during aging. Methods: We measure changes in mitochondrial morphology and mitochondrial connectivity during the aging of the mouse gastrocnemius muscle through serial block facing-scanning electron microscopy and 3D reconstruction. Nanotunnels are also measured through 3D reconstruction. CRISPR/Cas9 KD is performed to examine changes in mitochondria upon loss of MICOS complex and OPA-1. Metabolomics are used to find key metabolite pathways changed upon MICOS complex loss. Results: We found changes in mitochondrial network configuration, nanotunneling, size, shape, number, contact sites, and cristae organizing system (MICOS) dynamics and gene expression in skeletal muscle across aging. Cardiac muscle showed similar differences but less fragmentation and wide-spread changes across 2-year aaging. We also found an association of optic atrophy 1 (OPA-1) and the MICOS complex in the gastrocnemius with mitochondrial aging, decreased oxidative capacity, and altered mitochondrial metabolism. Conclusions: We are the first to examine mitochondria changes in skeletal muscle and cardiac muscle across aging. 3D reconstructions of nanotunnels elucidated novel patterns in skeletal muscle. Notably, we noticed differences in skeletal and cardiac muscle that suggests a differential response to mitochondrial aging in cardiac and skeletal muscle. Importantly, we found similar changes in mitochondrial morphology were observed in aging skeletal muscles and for loss of MICOS proteins in mouse skeletal muscle. Furthermore, MICOS proteins decreased with age. In tandem, this suggests a relationship between the MICOS complex and aging, which further 3D reconstruction could potentially further link to disease states.

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Section: Resultssupporting

confidence: 85%

3D Reconstruction of Murine Mitochondria Exhibits Changes in Structure Across Aging Linked to the MICOS Complex

Vue

Lopez

Neikirk

et al. 2022

Preprint

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“…Our study demonstrated that, after intervention, the LBMP and SMMP significantly increased, indicating that the weight reduction does not cause concomitant loss of muscle mass after dulaglutide treatment, and our results were consistent with previous animal studies. 18 …”

Section: Discussionmentioning

confidence: 99%

Assessment of Changes in Body Composition After 3 Months of Dulaglutide Treatment

Chen,

Wang,

Jin

et al. 2024

DMSO

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Background Changes in body composition accompanied by glucagon-like peptide 1 receptor agonist (GLP-1RA) induced weight loss have drawn much attention. However, fewer studies have reported body composition changes in patients receiving dulaglutide therapy in Chinese population. Methods A total of 70 overweight/obese type 2 diabetes mellitus (T2DM) patients who received dulaglutide therapy were included. Clinical data were collected. Visceral fat area (VFA) and body composition were also measured. Changes in clinical indicators and body composition of patients before and after intervention were also analyzed. Correlation analysis and multiple linear regression model were used to evaluate the association between hemoglobin A1C (HbA1c) and body composition. Results The results showed that body weight (BW), VFA, body fat (BF), lean body mass (LBM), skeletal muscle mass (SMM) and water content were reduced after 3 months dulaglutide intervention. The lean body mass percentage (LBMP) and skeletal muscle mass percentage (SMMP) significantly increased. Moreover, there was no significant difference in bone mineral quality (BMQ) after the intervention. The multiple linear regression model revealed that the % change in BF was independently associated with % change in HbA1c (β = 0.449, t = 3.148, p=0.002). Conclusion These results indicate that dulaglutide intervention does not cause muscle and bone mass loss while inducing weight loss, and % change in BF was independently associated with improved glucose control during dulaglutide therapy. This study offers some positive results to support the clinical application of dulaglutide.

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“…In another study, Khin et al [139] investigated whether dulaglutide could present a therapeutic potential against muscle wasting due to aging in mice. The researchers affirmed that the GLP-1A improved muscle mass and muscle strength in the aged mice, helping improve histopathological parameters by an increased shift toward middle and large-sized skeletal muscle fibers.…”

Section: Glucagon-like Peptide-1 Receptor Agonists (Glp-1a)mentioning

confidence: 99%

Insights into Pathogenesis, Nutritional and Drug Approach in Sarcopenia: A Systematic Review

et al. 2023

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Sarcopenia is a multifactorial condition related to the loss of muscle mass and strength due to aging, eating habits, physical inactivity, or even caused by another disease. Affected individuals have a higher risk of falls and may be associated with heart disease, respiratory diseases, cognitive impairment, and consequently an increased risk of hospitalization, in addition to causing an economic impact due to the high cost of care during the stay in hospitals. The standardization of appropriate treatment for patients with sarcopenia that could help reduce pathology-related morbidity is necessary. For these reasons, this study aimed to perform a systematic review of the role of nutrition and drugs that could ameliorate the health and quality of life of sarcopenic patients and PRISMA guidelines were followed. Lifestyle interventions have shown a profound impact on sarcopenia treatment but using supplements and different drugs can also impact skeletal muscle maintenance. Creatine, leucine, branched-chain amino acids, omega 3, and vitamin D can show benefits. Although with controversial results, medications such as Metformin, GLP-1, losartan, statin, growth hormone, and dipeptidyl peptidase 4 inhibitors have also been considered and can alter the sarcopenic’s metabolic parameters, protect against cardiovascular diseases and outcomes, while protecting muscles.

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Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice

Cited by 15 publications

References 41 publications

3D Reconstruction of Murine Mitochondria Exhibits Changes in Structure Across Aging Linked to the MICOS Complex

3D Reconstruction of Murine Mitochondria Exhibits Changes in Structure Across Aging Linked to the MICOS Complex

Assessment of Changes in Body Composition After 3 Months of Dulaglutide Treatment

Insights into Pathogenesis, Nutritional and Drug Approach in Sarcopenia: A Systematic Review

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