Exercise early in life in rats born small does not normalize reductions in skeletal muscle PGC-1α in adulthood

We have previously shown that 4 wk of exercise training early in life normalizes the otherwise greatly reduced pancreatic β-cell mass in adult male rats born small. The aim of the current study was to determine whether a similar normalization in adulthood of reduced skeletal muscle mitochondrial biogenesis markers and alterations in skeletal muscle lipids of growth-restricted male rats occurs following early exercise training. Bilateral uterine vessel ligation performed on day 18 of gestation resulted in Restricted offspring born small ( P < 0.05) compared with both sham-operated Controls and a sham-operated Reduced litter group. Offspring remained sedentary or underwent treadmill running from 5–9 (early exercise) or 20–24 (later exercise) wk of age. At 24 wk of age, Restricted and Reduced litter offspring had lower ( P < 0.05) skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein expression compared with Control offspring. Early exercise training had the expected effect of increasing skeletal muscle markers of mitochondrial biogenesis, but, at this early age (9 wk), there was no deficit in Restricted and Reduced litter skeletal muscle mitochondrial biogenesis. Unlike our previous observations in pancreatic β-cell mass, there was no “reprogramming” effect of early exercise on adult skeletal muscle such that PGC-1α was lower in adult Restricted and Reduced litter offspring irrespective of exercise training. Later exercise training increased mitochondrial biogenesis in all groups. In conclusion, although the response to exercise training remains intact, early exercise training in rats born small does not have a reprogramming effect to prevent deficits in skeletal muscle markers of mitochondrial biogenesis in adulthood.

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Short-term exercise training early in life restores deficits in pancreatic β-cell mass associated with growth restriction in adult male rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00114.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. E931-E940 ◽

Cited By ~ 37

Author(s):

Rhianna C. Laker ◽

Linda A. Gallo ◽

Mary E. Wlodek ◽

Andrew L. Siebel ◽

Glenn D. Wadley ◽

...

Keyword(s):

Exercise Training ◽

Glucose Tolerance ◽

Adult Male ◽

Early Life ◽

Cell Mass ◽

Growth Restriction ◽

Treadmill Running ◽

Male Rats ◽

Pancreatic Β Cell ◽

Β Cell

Fetal growth restriction is associated with reduced pancreatic β-cell mass, contributing to impaired glucose tolerance and diabetes. Exercise training increases β-cell mass in animals with diabetes and has long-lasting metabolic benefits in rodents and humans. We studied the effect of exercise training on islet and β-cell morphology and plasma insulin and glucose, following an intraperitoneal glucose tolerance test (IPGTT) in juvenile and adult male Wistar-Kyoto rats born small. Bilateral uterine vessel ligation performed on day 18 of pregnancy resulted in Restricted offspring born small compared with sham-operated Controls and also sham-operated Reduced litter offspring that had their litter size reduced to five pups at birth. Restricted, Control, and Reduced litter offspring remained sedentary or underwent treadmill running from 5 to 9 or 20 to 24 wk of age. Early life exercise increased relative islet surface area and β-cell mass across all groups at 9 wk, partially restoring the 60–68% deficit ( P < 0.05) in Restricted offspring. Remarkably, despite no further exercise training after 9 wk, β-cell mass was restored in Restricted at 24 wk, while sedentary littermates retained a 45% deficit ( P = 0.05) in relative β-cell mass. Later exercise training also restored Restricted β-cell mass to Control levels. In conclusion, early life exercise training in rats born small restored β-cell mass in adulthood and may have beneficial consequences for later metabolic health and disease.

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Age-associated declines in mitochondrial biogenesis and protein quality control factors are minimized by exercise training

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00337.2011 ◽

2012 ◽

Vol 303 (2) ◽

pp. R127-R134 ◽

Cited By ~ 81

Author(s):

Erika Koltai ◽

Nikolett Hart ◽

Albert W. Taylor ◽

Sataro Goto ◽

Jenny K. Ngo ◽

...

Keyword(s):

Skeletal Muscle ◽

Quality Control ◽

Exercise Training ◽

Mitochondrial Biogenesis ◽

Protein Quality ◽

Mitochondrial Protein ◽

Protein Quality Control ◽

Treadmill Running ◽

Common Finding ◽

Moderate Intensity

A decline in mitochondrial biogenesis and mitochondrial protein quality control in skeletal muscle is a common finding in aging, but exercise training has been suggested as a possible cure. In this report, we tested the hypothesis that moderate-intensity exercise training could prevent the age-associated deterioration in mitochondrial biogenesis in the gastrocnemius muscle of Wistar rats. Exercise training, consisting of treadmill running at 60% of the initial V̇o2max, reversed or attenuated significant age-associated (detrimental) declines in mitochondrial mass (succinate dehydrogenase, citrate synthase, cytochrome- c oxidase-4, mtDNA), SIRT1 activity, AMPK, pAMPK, and peroxisome proliferator-activated receptor gamma coactivator 1-α, UCP3, and the Lon protease. Exercise training also decreased the gap between young and old animals in other measured parameters, including nuclear respiratory factor 1, mitochondrial transcription factor A, fission-1, mitofusin-1, and polynucleotide phosphorylase levels. We conclude that exercise training can help minimize detrimental skeletal muscle aging deficits by improving mitochondrial protein quality control and biogenesis.

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Androgen signaling expands β-cell mass in male rats and β-cell androgen receptor is degraded under high-glucose conditions

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00211.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. E274-E286 ◽

Cited By ~ 8

Author(s):

Naoki Harada ◽

Yasuhiro Yoda ◽

Yusuke Yotsumoto ◽

Tatsuya Masuda ◽

Yuji Takahashi ◽

...

Keyword(s):

Androgen Receptor ◽

Cell Mass ◽

Calcium Ionophore ◽

Calcium Ionophore A23187 ◽

Male Rats ◽

Ionophore A23187 ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Ki 67

A deficient pancreatic β-cell mass increases the risk of type 2 diabetes mellitus. Here, we investigated the effects of testosterone on the development of pancreatic β-cell mass in male rats. The β-cell mass of male rats castrated at 6 wk of age was reduced to ~30% of that of control rats at 16 wk of age, and castration caused glucose intolerance. Loss of β-cell mass occurred because of decreases in islet density per pancreas and β-cell cluster size. Castration was negatively associated with the number of Ki-67-positive β-cells and positively associated with the number of TUNEL-positive β-cells. These β-cell changes could be prevented by testosterone treatment. In contrast, castration did not affect β-cell mass in male mice. Androgen receptor (AR) localized differently in mouse and rat β-cells. Testosterone enhanced the viability of INS-1 and INS-1 #6, which expresses high levels of AR, in rat β-cell lines. siRNA-mediated AR knockdown or AR antagonism with hydroxyflutamide attenuated this enhancement. Moreover, testosterone did not stimulate INS-1 β-cell viability under high d-glucose conditions. In INS-1 β-cells, d-glucose dose dependently (5.5–22.2 mM) downregulated AR protein levels both in the presence and absence of testosterone. The intracellular calcium chelator (BAPTA-AM) could prevent this decrease in AR expression. AR levels were also reduced by a calcium ionophore (A23187), but not by insulin, in the absence of the proteasome inhibitor MG132. Our results indicate that testosterone regulates β-cell mass, at least in part, by AR activation in the β-cells of male rats and that the β-cell AR is degraded under hyperglycemic conditions.

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Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00227.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. E1018-E1029 ◽

Cited By ~ 26

Author(s):

Colby B. Tanner ◽

Steven R. Madsen ◽

David M. Hallowell ◽

Darren M. J. Goring ◽

Timothy M. Moore ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Protein Content ◽

Exercise Capacity ◽

Citrate Synthase ◽

Pyruvate Dehydrogenase Kinase ◽

Treadmill Running ◽

Mitochondrial Proteins ◽

Running Performance ◽

Early Exercise

LKB1 and its downstream targets of the AMP-activated protein kinase family are important regulators of many aspects of skeletal muscle cell function, including control of mitochondrial content and capillarity. LKB1 deficiency in skeletal and cardiac muscle (mLKB1-KO) greatly impairs exercise capacity. However, cardiac dysfunction in that genetic model prevents a clear assessment of the role of skeletal muscle LKB1 in the observed effects. Our purposes here were to determine whether skeletal muscle-specific knockout of LKB1 (skmLKB1-KO) decreases exercise capacity and mitochondrial protein content, impairs accretion of mitochondrial proteins after exercise training, and attenuates improvement in running performance after exercise training. We found that treadmill and voluntary wheel running capacity was reduced in skmLKB1-KO vs. control (CON) mice. Citrate synthase activity, succinate dehydrogenase activity, and pyruvate dehydrogenase kinase content were lower in KO vs. CON muscles. Three weeks of treadmill training resulted in significantly increased treadmill running performance in both CON and skmLKB1-KO mice. Citrate synthase activity increased significantly with training in both genotypes, but protein content and activity for components of the mitochondrial electron transport chain increased only in CON mice. Capillarity and VEGF protein was lower in skmLKB1-KO vs. CON muscles, but VEGF increased with training only in skmLKB1-KO. Three hours after an acute bout of muscle contractions, PGC-1α, cytochrome c, and VEGF gene expression all increased in CON but not skmLKB1-KO muscles. Our findings indicate that skeletal muscle LKB1 is required for accretion of some mitochondrial proteins but not for early exercise capacity improvements with exercise training.

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Fetal androgen signaling defects affect pancreatic β-cell mass and function, leading to glucose intolerance in high-fat diet-fed male rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00173.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. E731-E741 ◽

Cited By ~ 4

Author(s):

Naoki Harada ◽

Yusuke Yotsumoto ◽

Takahiro Katsuki ◽

Yasuhiro Yoda ◽

Tatsuya Masuda ◽

...

Keyword(s):

Glucose Intolerance ◽

High Fat Diet ◽

Cell Function ◽

Cell Mass ◽

Male Rats ◽

Standard Diet ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Β Cell Function

We previously demonstrated that androgen signaling expands pancreatic β-cell mass in the sexual maturation period ( Am J Physiol Endocrinol Metab 314: E274–E286, 2018). The aim of this study was to elucidate whether fetal androgen signaling plays important roles in β-cell mass development and β-cell function in adulthood, defects of which are associated with type 2 diabetes mellitus. In the pancreas of male fetuses, androgen receptor (AR) was strongly expressed in the cytoplasm and at the cell membrane of Nkx6.1-positive β-cell precursor cells but was markedly reduced in insulin-positive β-cells. Administration of the anti-androgen flutamide to pregnant dams during late gestation reduced β-cell mass and Ki67-positive proliferating β-cells at birth in a male-specific manner without affecting body weight. The decrease of β-cell mass in flutamide-exposed male rats was not recovered when rats were fed a standard diet, whereas it was fully recovered when rats were fed a high-fat diet (HFD), at 6 and 12 wk of age. Flutamide exposure in utero led to the development of glucose intolerance in male rats due to a decrease in insulin secretion when fed HFD but not standard diet. Insulin sensitivity did not differ between the two groups irrespective of diet. These results indicated that the action of fetal androgen contributed to β-cell mass expansion in a sex-specific manner at birth and to the development of glucose intolerance by decreasing the secretion of insulin in HFD-fed male rats. Our data demonstrated the involvement of fetal androgen signaling in hypothesized sex differences in the developmental origins of health and disease by affecting pancreatic β-cell function.

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The Effect of Dietary Fat on Insulin Secretion and Pancreatic β-Cell Mass in 90% Pancreatectomized Diabetic Rats

Journal of the Korean Society of Food Science and Nutrition ◽

10.3746/jkfn.2007.36.2.186 ◽

2007 ◽

Vol 36 (2) ◽

pp. 186-193 ◽

Cited By ~ 1

Author(s):

Sun-Min Park ◽

Chun-Hee Park ◽

Sang-Mee Hong

Keyword(s):

Insulin Secretion ◽

Dietary Fat ◽

Cell Mass ◽

Diabetic Rats ◽

Pancreatic Β Cell ◽

Β Cell

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Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

Scientific Reports ◽

10.1038/s41598-021-94725-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Brenda Strutt ◽

Sandra Szlapinski ◽

Thineesha Gnaneswaran ◽

Sarah Donegan ◽

Jessica Hill ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Glucose Transporter ◽

Cell Mass ◽

Elevated Serum ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Transporter 2 ◽

Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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