Diabetic Muscular Atrophy: Molecular Mechanisms and Promising Therapies

Shen, Yuntian; Li, Ming; Wang, Kexin; Qi, Guangdong; Liu, Hua; Wang, Wei; Ji, Yanan; Chang, Mengyuan; Deng, Chao; Xing, Feng; Shen, Mi; Sun, Hualin

doi:10.3389/fendo.2022.917113

Cited by 45 publications

(39 citation statements)

References 118 publications

(136 reference statements)

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“…1,2 Skeletal muscle plays an indispensable role in overall health as the primary organ of postprandial insulin stimulated glucose uptake and a significant contributor to whole body metabolic rate. Metabolic perturbations impact muscle mass, 3 suggesting that strategies targeting mitochondrial metabolism could be an effective way to mitigate or reverse obesity 4 including sarcopenic obesity, 5 type 2 diabetes induced muscle atrophy, 3 and cancer cachexia mitochondrial dysfunction. 6,7 Exercise is a prime intervention that improves muscle metabolic health in disease 8,9 ; however, vigorous exercise may not be possible in all patients due to their existing comorbidities.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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Gene expression of the NR4A nuclear orphan receptor NOR‐1 is reduced in obesity and in human skeletal muscle during disuse. It has been well established that NOR‐1 is highly responsive to both aerobic and resistance exercise and NOR‐1 overexpression is coincident with a plethora of metabolic benefits. However, it is unclear whether loss of NOR‐1 contributes to inappropriate metabolic signaling in skeletal muscle that could lead to insulin resistance. The purpose of this study was to elucidate the impact of NOR‐1 deficiency on C2C12 metabolic signaling. Changes in gene expression after siRNA‐mediated NOR‐1 knockdown in C2C12 myotubes were determined by qPCR and bioinformatic analysis of RNA‐Seq data. Our RNA‐Seq data identified several metabolic targets regulated by NOR‐1 and implicates NOR‐1 as a modulator of mTORC1 signaling via Akt‐independent mechanisms. Furthermore, pathway analysis revealed NOR‐1 knockdown perturbs the insulin resistance and insulin sensitivity pathways. Taken together, these data suggest skeletal muscle NOR‐1 deficiency may contribute to altered metabolic signaling that is consistent with metabolic disease. We postulate that strategies that improve NOR‐1 may be important to offset the negative impact that inactivity, obesity, and type 2 diabetes have on mitochondria and muscle metabolism.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“…[32] . Muscle wasting can occur as a result of metabolic imbalances such as starvation, weightlessness, or diabetes [33,34] . These imbalances disrupt protein anabolism and catabolism, leading to secondary muscle loss [35] .…”

Section: Discussionmentioning

confidence: 99%

No Evidence of Causal Effects between Renal Impairment and Muscle Wasting: a Two-Sample Mendelian Randomization Study

Wang,

Jin,

Zhang

et al. 2024

Preprint

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Background Numerous investigations have explored the potential correlation between renal impairment and muscle loss. However, the establishment of a definitive cause-and-effect relationship between these two remains elusive.Methods We utilized genome-wide association studies summary data from the CKDGen Consortium to identify genetically predicted estimated Glomerular Filtration Rate (eGFR), chronic kidney disease (CKD), and blood urea nitrogen (BUN) involving 567,460, 480,698, and 234,029 participants, respectively. To evaluate site-specific genetically predicted muscle mass, data from the UK Biobank were employed (n ≤ 454,835). The primary analysis relied on the inverse-variance weighted (IVW) method, with additional sensitivity analyses performed to validate the robustness of the MR results.Results No significant evidence could support that genetically predicted CKD was associated with appendicular and trunk muscle wasting [right leg FFM: IVW odds ratio (OR) = 1.010, confidence interval (CI) = 0.989 to 1.032, P-value = 0.355; left leg FFM: IVW OR = 1.009, CI = 0.988 to 1.031, P-value = 0.381; right arm FFM: IVW OR = 1.012, CI = 0.992 to 1.033, P-value = 0.231; left arm FFM: IVW OR = 1.010, CI = 0.990 to 1.030, P-value = 0.320; trunk FFM: IVW OR = 1.012, CI = 0.991 to 1.033, P-value = 0.279]. Similar estimations could also be observed in MR analyses of eGFR and BUN on muscle mass.Conclusions It is unlikely that genetically predicted renal impairment can causally increase the risk of muscle wasting. Clinically observed associations in epidemiologic studies might be attributed to metabolic homeostasis imbalances stemming from renal impairment.

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“…Patients with T2DM or obesity are prone to muscle atrophy, which has a detrimental effect on their daily activities and quality of life and may shorten their life expectancy 81 . Imbalance in protein synthesis and degradation is the underlying cause of muscle atrophy, and obesity and long‐term nutritional excess are associated with insulin resistance and chronic inflammation, ultimately impeding the growth of muscle fibres 82 . Recent studies have identified three proteins belonging to the TRIM family that impact myofibre growth or differentiation: TRIM32 and TRIM72 regulate muscle differentiation by controlling the PI3K subunit p85 and IRS‐1‐AKT signalling pathways, while TRIM63 may contribute to myasthenia gravis by increasing oxidative stress and muscle catabolism.…”

Section: Mechanisms Of Trim Proteins In Diabetes and Its Complicationsmentioning

confidence: 99%

Role of the tripartite motif‐containing (TRIM) family of proteins in insulin resistance and related disorders

Chen,

Feng,

Zhou

et al. 2023

Diabetes Obesity Metabolism

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Emerging evidence suggests that the ubiquitin‐mediated degradation of insulin‐signalling‐related proteins may be involved in the development of insulin resistance and its related disorders. Tripartite motif‐containing (TRIM) proteins, a superfamily belonging to the E3 ubiquitin ligases, are capable of controlling protein levels and function by ubiquitination, which is essential for the modulation of insulin sensitivity. Recent research has indicated that some of these TRIMs act as key regulatory factors of metabolic disorders such as type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, and atherosclerosis. This review provides a comprehensive overview of the latest evidence linking TRIMs to the regulation of insulin resistance and its related disorders, their roles in regulating multiple signalling pathways or cellular processes, such as insulin signalling pathways, peroxisome proliferator‐activated receptor signalling pathways, glucose and lipid metabolism, the inflammatory response, and cell cycle control, as well as recent advances in the development of TRIM‐targeted drugs.

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Diabetic Muscular Atrophy: Molecular Mechanisms and Promising Therapies

Cited by 45 publications

References 118 publications

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

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

No Evidence of Causal Effects between Renal Impairment and Muscle Wasting: a Two-Sample Mendelian Randomization Study

Role of the tripartite motif‐containing (TRIM) family of proteins in insulin resistance and related disorders

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