IGF2 deficiency causes mitochondrial defects in skeletal muscle

Zhu, Yiyi; Gui, Weiwei; Tan, Bowen; Du, Ying; Zhou, Jian; Wu, Fang; Li, Hong; Lin, Xihua

doi:10.1042/cs20210128

Cited by 15 publications

(13 citation statements)

References 25 publications

(27 reference statements)

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“…Still, several genes encoding proteins known to induce mitochondrial biogenesis have been shown to increase expression after exercise, e.g., CAMK2A and CAMK2B (Table S 1 ) [ 22 , 23 ]. A recent study indicates that IGF2 also promotes mitochondrial biogenesis in skeletal muscle [ 24 ], and similar results have been obtained for IGF1 [ 25 – 27 ], and both transcripts increase after exercise (Table S 1 ). Although pathways for mitochondrial biogenesis were not over-represented after the intervention, those involved in vasculogenesis and angiogenesis were highly upregulated with resistance training.…”

Section: Discussionsupporting

confidence: 81%

Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults

Gautvik

Olstad

Raue

et al. 2022

Eur Rev Aging Phys Act

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Background A striking effect of old age is the involuntary loss of muscle mass and strength leading to sarcopenia and reduced physiological functions. However, effects of heavy-load exercise in older adults on diseases and functions as predicted by changes in muscle gene expression have been inadequately studied. Methods Thigh muscle global transcriptional activity (transcriptome) was analyzed in cohorts of older and younger adults before and after 12–13 weeks heavy-load strength exercise using Affymetrix microarrays. Three age groups, similarly trained, were compared: younger adults (age 24 ± 4 years), older adults of average age 70 years (Oslo cohort) and above 80 years (old BSU cohort). To increase statistical strength, one of the older cohorts was used for validation. Ingenuity Pathway analysis (IPA) was used to identify predicted biological effects of a gene set that changed expression after exercise, and Principal Component Analysis (PCA) was used to visualize differences in muscle gene expressen between cohorts and individual participants as well as overall changes upon exercise. Results Younger adults, showed few transcriptome changes, but a marked, significant impact was observed in persons of average age 70 years and even more so in persons above 80 years. The 249 transcripts positively or negatively altered in both cohorts of older adults (q-value < 0.1) were submitted to gene set enrichment analysis using IPA. The transcripts predicted increase in several aspects of “vascularization and muscle contractions”, whereas functions associated with negative health effects were reduced, e.g., “Glucose metabolism disorder” and “Disorder of blood pressure”. Several genes that changed expression after intervention were confirmed at the genome level by containing single nucleotide variants associated with handgrip strength and muscle expression levels, e.g., CYP4B1 (p = 9.2E-20), NOTCH4 (p = 9.7E-8), and FZD4 (p = 5.3E-7). PCA of the 249 genes indicated a differential pattern of muscle gene expression in young and elderly. However, after exercise the expression patterns in both young and old BSU cohorts were changed in the same direction for the vast majority of participants. Conclusions The positive impact of heavy-load strength training on the transcriptome increased markedly with age. The identified molecular changes translate to improved vascularization and muscular strength, suggesting highly beneficial health effects for older adults.

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Section: Discussionsupporting

confidence: 81%

Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults

Gautvik

Olstad

Raue

et al. 2022

Eur Rev Aging Phys Act

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“…6 C). An in vitro study has demonstrated the potential involvement of IGF2 in improving the mitochondrial structure of muscle cells in the culture medium [ 44 ]. Thus, these findings suggest that IGF2 treatment can improve the mitochondrial function of oocytes from obese mice by somehow improving mitochondrial ultrastructure.…”

Section: Resultsmentioning

confidence: 99%

IGF2 reduces meiotic defects in oocytes from obese mice and improves embryonic developmental competency

Wan

Muhammad

Huang

et al. 2022

Reprod Biol Endocrinol

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Background Maternal obesity is a global issue that has devastating effects across the reproductive spectrum such as meiotic defects in oocytes, consequently worsening pregnancy outcomes. Different studies have shown that such types of meiotic defects originated from the oocytes of obese mothers. Thus, there is an urgent need to develop strategies to reduce the incidence of obesity-related oocyte defects that adversely affect pregnancy outcomes. Multiple growth factors have been identified as directly associated with female reproduction; however, the impact of various growth factors on female fertility in response to obesity remains poorly understood. Methods The immature GV-stage oocytes from HFD female mice were collected and cultured in vitro in two different groups (HFD oocytes with and without 50 nM IGF2), however; the oocytes from ND mice were used as a positive control. HFD oocytes treated with or without IGF2 were further used to observe the meiotic structure using different analysis including, the spindle and chromosomal analysis, reactive oxygen species levels, mitochondrial functional activities, and early apoptotic index using immunofluorescence. Additionally, the embryonic developmental competency and embryos quality of IGF2-treated zygotes were also determined. Results In our findings, we observed significantly reduced contents of insulin-like growth factor 2 (IGF2) in the serum and oocytes of obese mice. Our data indicated supplementation of IGF2 in a culture medium improves the blastocyst formation: from 46% in the HFD group to 61% in the HFD + IGF2-treatment group (50 nM IGF2). Moreover, adding IGF2 to the culture medium reduces the reactive oxygen species index and alleviates the frequency of spindle/chromosome defects. We found increased mitochondrial functional activity in oocytes from obese mice after treating the oocytes with IGF2: observed elevated level of adenosine triphosphate, increased mitochondrial distribution, higher mitochondrial membrane potentials, and reduced mitochondrial ultrastructure defects. Furthermore, IGF2 administration also increases the overall protein synthesis and decreases the apoptotic index in oocytes from obese mice. Conclusions Collectively, our findings are strongly in favor of adding IGF2 in culture medium to overcome obesity-related meiotic structural-developmental defects by helping ameliorate the known sub-optimal culturing conditions that are currently standard with assisted reproduction technologies.

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“…IGF2 is a promyogenic protein that is important for muscle development as well as fetal and post-natal growth, and it also functions in muscle recovery and nerve regeneration after injury ( 18 ). IGF2 deletion in skeletal muscle cells reduces mitochondrial biogenesis, mitochondria-associated protein content, and mitochondrial function ( 40 ). Studies have also shown that increased IGF2 expression promotes the intramuscular lipid content of porcine skeletal muscle ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes and infiltrating immune cells in skeletal muscle in obesity

Jin¹,

Huang²,

Chen³

et al. 2022

Ann Transl Med

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Background: Metabolic syndrome (MetS) refers to a cluster of metabolic disorders that are mainly caused by obesity. Skeletal muscle is a central component of systemic metabolism. However, the mechanism of skeletal muscle metabolic impairment in obesity remains unclear. This study aimed to identify key early biomarkers in skeletal muscle for the prevention and treatment of MetS in obesity. Methods:The GSE85439 dataset was downloaded from the Gene Expression Omnibus database.Gene set enrichment and immune cell infiltration analyses were performed for genome-wide genes.Differentially expressed genes (DEGs) between obese and control mice were screened and subjected to functional enrichment analysis, and a protein-protein interaction network was constructed. The results of the bioinformatics analysis were confirmed by immunofluorescence and real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR).Results: Enrichment analysis indicated that the genes expressed in obese mice were mainly associated with acute inflammatory response. Immune cell infiltration analysis of 190 DEGs with consistent trends showed that the numbers of mast cells (MCs) and active dendritic cells were significantly higher in obese mice than in control mice. Immunofluorescence analysis confirmed that the number of MCs present in the skeletal muscle was higher in obese mice than in control mice, although no difference was observed in the active dendritic cell count. Functional enrichment analysis showed that the DEGs were mainly associated with transcriptional regulation. In the clusters of the protein-protein interaction network, four acute-phaseresponse genes (SAA1, SAA2, ORM1, and HP) were significantly correlated with transcription-regulating genes (SHH, IGF2, and CELA1); these seven genes were identified as hub genes. The qRT-PCR results showed that the expression levels of SAA1, SAA2, IGF2, and CELA1 were significantly higher in obese mice than in control mice; however, those of HP, ORM1, and SHH did not differ significantly between the two groups. Conclusions:The skeletal muscle of obese mice exhibits elevated MC infiltration and increased SAA1, SAA2, CELA1, and IGF2 expression. The identification of these biomarkers has increased our understanding of the potential functional mechanisms of skeletal muscle in obesity. These potential biomarkers may serve as targets for the prevention and treatment of MetS.

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IGF2 deficiency causes mitochondrial defects in skeletal muscle

Cited by 15 publications

References 25 publications

Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults

Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults

IGF2 reduces meiotic defects in oocytes from obese mice and improves embryonic developmental competency

Identification of hub genes and infiltrating immune cells in skeletal muscle in obesity

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