Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG

ABSTRACTThe peroxisome-proliferator activated receptors (PPARs) have been previously implicated in the pathophysiology of skeletal muscle dysfunction in women with breast cancer (BC) and in animal models of BC. Here, we sought to describe the metabolic alterations induced in skeletal muscle by BC-derived factors in an in vitro conditioned media (CM) system and hypothesized that BC cells secrete a factor that represses PPAR-gamma (PPARG) expression and its transcriptional activity, leading to downregulation of PPARG target genes involved in mitochondrial function and other metabolic pathways. We found that BC-derived factors repress PPAR-mediated transcriptional activity without altering protein expression of PPARG. Further, we show that BC-derived factors induce significant alterations in skeletal muscle mitochondrial function and lipid metabolism, which are rescued with exogenous expression of PPARG. The PPARG agonist drug rosiglitazone was able to rescue BC-induced lipid accumulation, but did not rescue effects of BC-derived factors on PPAR-mediated transcription or mitochondrial function. These data suggest that BC-derived factors induce deficits in lipid metabolism and mitochondrial function via different mechanisms that are both related to PPARG signaling, with mitochondrial dysfunction likely being altered via repression of PPAR-mediated transcription, and lipid accumulation being altered via transcription-independent functions of PPARG.

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Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG

AJP Cell Physiology ◽

10.1152/ajpcell.00264.2020 ◽

2021 ◽

Author(s):

Hannah E. Wilson ◽

David A. Stanton ◽

Stephanie Rellick ◽

Werner Geldenhuys ◽

Emidio E. Pistilli

Keyword(s):

Breast Cancer ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Lipid Accumulation ◽

Transcriptional Activity ◽

Target Genes ◽

Ppar Gamma ◽

Peroxisome Proliferator ◽

Independent Functions

The peroxisome-proliferator activated receptors (PPARs) have been previously implicated in the pathophysiology of skeletal muscle dysfunction in women with breast cancer (BC) and in animal models of BC. This study investigated alterations induced in skeletal muscle by BC-derived factors in an in vitro conditioned media (CM) system and tested the hypothesis that BC cells secrete a factor that represses PPAR-gamma (PPARG) expression and its transcriptional activity, leading to downregulation of PPARG target genes involved in mitochondrial function and other metabolic pathways. We found that BC-derived factors repress PPAR-mediated transcriptional activity without altering protein expression of PPARG. Further, we show that BC-derived factors induce significant alterations in skeletal muscle mitochondrial function and lipid accumulation, which are rescued with exogenous expression of PPARG. The PPARG agonist drug rosiglitazone was able to rescue BC-induced lipid accumulation, but did not rescue effects of BC-derived factors on PPAR-mediated transcription or mitochondrial function. These data suggest that BC-derived factors alter lipid accumulation and mitochondrial function via different mechanisms that are both related to PPARG signaling, with mitochondrial dysfunction likely being altered via repression of PPAR-mediated transcription, and lipid accumulation being altered via transcription-independent functions of PPARG.

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Intramyocellular Lipid Accumulation After High-Fat Diet Is Associated with the Gene Expression Involved in Lipid Metabolism in Skeletal Muscle of Non-Obese Men

Juntendo Medical Journal ◽

10.14789/jmj.62.s144 ◽

2016 ◽

Vol 62 (Suppl.1) ◽

pp. 144-145

Author(s):

SAORI KAKEHI ◽

YOSHIFUMI TAMURA ◽

KAGEUMI TAKENO ◽

YUKO SAKURAI ◽

MINAKO KAWAGUCHI ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Lipid Metabolism ◽

Lipid Accumulation ◽

High Fat Diet ◽

Intramyocellular Lipid ◽

High Fat

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UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00434.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. E347-E353 ◽

Cited By ~ 33

Author(s):

Dong-Ho Han ◽

Lorraine A. Nolte ◽

Jeong-Sun Ju ◽

Trey Coleman ◽

John O. Holloszy ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Glucose Transport ◽

Lipid Accumulation ◽

Uncoupling Protein ◽

Serum Glucose ◽

Mineral Density ◽

Beneficial Effects ◽

High Level

To address the potential role of lipotoxicity and mitochondrial function in insulin resistance, we studied mice with high-level expression of uncoupling protein-1 in skeletal muscle (UCP-H mice). Body weight, body length, and bone mineral density were decreased in UCP-H mice compared with wild-type littermates. Forelimb grip strength and muscle mass were strikingly decreased, whereas muscle triglyceride content was increased fivefold in UCP-H mice. Electron microscopy demonstrated lipid accumulation and large mitochondria with abnormal architecture in UCP-H skeletal muscle. ATP content and key mitochondrial proteins were decreased in UCP-H muscle. Despite mitochondrial dysfunction and increased intramyocellular fat, fasting serum glucose was 22% lower and insulin-stimulated glucose transport 80% higher in UCP-H animals. These beneficial effects on glucose metabolism were associated with increased AMP kinase and hexokinase activities, as well as elevated levels of GLUT4 and myocyte enhancer factor-2 proteins A and D in skeletal muscle. These results suggest that UCP-H mice have a mitochondrial myopathy due to depleted energy stores sufficient to compromise growth and impair muscle function. Enhanced skeletal muscle glucose transport in this setting suggests that excess intramyocellular lipid and mitochondrial dysfunction are not sufficient to cause insulin resistance in mice.

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6‐Gingerol Improves Ectopic Lipid Accumulation, Mitochondrial Dysfunction, and Insulin Resistance in Skeletal Muscle of Ageing Rats: Dual Stimulation of the AMPK/PGC‐1α Signaling Pathway via Plasma Adiponectin and Muscular AdipoR1

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201800649 ◽

2019 ◽

Vol 63 (6) ◽

pp. 1800649 ◽

Cited By ~ 7

Author(s):

Li Liu ◽

Ling Yao ◽

Shang Wang ◽

Zhiwei Chen ◽

Tingli Han ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Signaling Pathway ◽

Lipid Accumulation ◽

Plasma Adiponectin ◽

Stimulation Of

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Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2012-0266 ◽

2013 ◽

Vol 38 (5) ◽

pp. 512-519 ◽

Cited By ~ 8

Author(s):

Andrea S. Cornford ◽

Alexander Hinko ◽

Rachael K. Nelson ◽

Ariel L. Barkan ◽

Jeffrey F. Horowitz

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Lipid Accumulation ◽

Rapid Development ◽

Insulin Response ◽

Whole Body ◽

Muscle Lipid ◽

Wet Weight

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ∼4000 kcals·day−1 (70 kcal·kg−1 fat free mass·day−1). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser312, Akt-Ser473, and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg−1 wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg−1 wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ∼35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating.

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PGC-1β prevents statin-associated myotoxicity in oxidative skeletal muscle

10.1101/218636 ◽

2017 ◽

Author(s):

François Singh ◽

Joffrey Zoll ◽

Urs Duthaler ◽

Anne-Laure Charles ◽

Gilles Laverny ◽

...

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Rat Skeletal Muscle ◽

Oxidative Defense ◽

Muscle Types ◽

And Function

AbstractStatins are generally well-tolerated, but can induce myopathy. Statins are associated with impaired expression of PGC-1β in human and rat skeletal muscle. The current study was performed to investigate the relation between PGC-1β expression and function and statin-associated myopathy. In WT mice, atorvastatin impaired mitochondrial function in glycolytic, but not in oxidative muscle. In PGC-1β KO mice, atorvastatin induced a shift from oxidative type IIA to glycolytic type IIB myofibers mainly in oxidative muscle and mitochondrial dysfunction was observed in both muscle types. In glycolytic muscle of WT and KO mice and in oxidative muscle of KO mice, atorvastatin suppressed mitochondrial proliferation and oxidative defense, leading to apoptosis. In contrast, mitochondrial function was maintained or improved and apoptosis decreased by atorvastatin in oxidative muscle of WT mice. In conclusion, PGC-1β has an important role in preventing damage to oxidative muscle in the presence of a mitochondrial toxicant such as atorvastatin.

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Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism

Lipids in Health and Disease ◽

10.1186/s12944-019-1145-x ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 5

Author(s):

Xi Cao ◽

Xin-Meng Lu ◽

Xiu Tuo ◽

Jing-Yi Liu ◽

Yi-Chen Zhang ◽

...

Keyword(s):

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Lipid Metabolism ◽

Er Stress ◽

Mitochondrial Function ◽

Knockout Mice ◽

Intramuscular Fat ◽

Muscle Lipid ◽

Angiotensin Converting Enzyme 2 ◽

Skeletal Muscle Lipid

Abstract Objective Endoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism. Methods The triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα, SREBP-1c, LXRα, CPT-1α, PGC-1α and PPARα), ER stress and mitochondrial function related genes (GRP78, eIF2α, ATF4, BCL-2, and SDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKβ/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice. Results ACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenous ACE2 improved lipid metabolism through the IKKβ/NFκB/IRS-1 pathway in skeletal muscle. Conclusions ACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.

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Skeletal Muscle Mitochondrial Dysfunction Is Present in Patients with CKD before Initiation of Maintenance Hemodialysis

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.10320819 ◽

2020 ◽

Vol 15 (7) ◽

pp. 926-936 ◽

Cited By ~ 4

Author(s):

Jorge L. Gamboa ◽

Baback Roshanravan ◽

Theodore Towse ◽

Chad A. Keller ◽

Aaron M. Falck ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Mitochondrial Dysfunction ◽

Physical Performance ◽

Mitochondrial Function ◽

Maintenance Hemodialysis ◽

Intermuscular Adipose Tissue ◽

Markers Of Inflammation ◽

And Oxidative Stress

Background and objectivesPatients with CKD suffer from frailty and sarcopenia, which is associated with higher morbidity and mortality. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. In this study, we tested the hypothesis that mitochondrial dysfunction is associated with the severity of CKD. We also evaluated the interaction between mitochondrial function and coexisting comorbidities, such as impaired physical performance, intermuscular adipose tissue infiltration, inflammation, and oxidative stress.Design, setting, participants, & measurements Sixty-three participants were studied, including controls (n=21), patients with CKD not on maintenance hemodialysis (CKD 3–5; n=20), and patients on maintenance hemodialysis (n=22). We evaluated in vivo knee extensors mitochondrial function using 31P magnetic resonance spectroscopy to obtain the phosphocreatine recovery time constant, a measure of mitochondrial function. We measured physical performance using the 6-minute walk test, intermuscular adipose tissue infiltration with magnetic resonance imaging, and markers of inflammation and oxidative stress in plasma. In skeletal muscle biopsies from a select number of patients on maintenance hemodialysis, we also measured markers of mitochondrial dynamics (fusion and fission).ResultsWe found a prolonged phosphocreatine recovery constant in patients on maintenance hemodialysis (53.3 [43.4–70.1] seconds, median [interquartile range]) and patients with CKD not on maintenance hemodialysis (41.5 [35.4–49.1] seconds) compared with controls (38.9 [32.5–46.0] seconds; P=0.001 among groups). Mitochondrial dysfunction was associated with poor physical performance (r=0.62; P=0.001), greater intermuscular adipose tissue (r=0.44; P=0.001), and increased markers of inflammation and oxidative stress (r=0.60; P=0.001). We found mitochondrial fragmentation and increased content of dynamin-related protein 1, a marker of mitochondrial fission, in skeletal muscles from patients on maintenance hemodialysis (0.86 [0.48–1.35] arbitrary units (A.U.), median [interquartile range]) compared with controls (0.60 [0.24–0.75] A.U.).ConclusionsMitochondrial dysfunction is due to multifactorial etiologies and presents prior to the initiation of maintenance hemodialysis, including in patients with CKD stages 3–5.

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Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1708037114 ◽

2017 ◽

Vol 114 (32) ◽

pp. 8596-8601 ◽

Cited By ~ 26

Author(s):

Wei Song ◽

Edward Owusu-Ansah ◽

Yanhui Hu ◽

Daojun Cheng ◽

Xiaochun Ni ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Target Genes ◽

Fat Body ◽

Mitochondrial Activity ◽

Rna Seq ◽

Mitochondria Dysfunction ◽

Activin Signaling ◽

Triglyceride Accumulation

Mitochondrial dysfunction has been associated with obesity and metabolic disorders. However, whether mitochondrial perturbation in a single tissue influences mitochondrial function and metabolic status of another distal tissue remains largely unknown. We analyzed the nonautonomous role of muscular mitochondrial dysfunction in Drosophila. Surprisingly, impaired muscle mitochondrial function via complex I perturbation results in simultaneous mitochondrial dysfunction in the fat body (the fly adipose tissue) and subsequent triglyceride accumulation, the major characteristic of obesity. RNA-sequencing (RNA-seq) analysis, in the context of muscle mitochondrial dysfunction, revealed that target genes of the TGF-β signaling pathway were induced in the fat body. Strikingly, expression of the TGF-β family ligand, Activin-β (Actβ), was dramatically increased in the muscles by NF-κB/Relish (Rel) signaling in response to mitochondrial perturbation, and decreasing Actβ expression in mitochondrial-perturbed muscles rescued both the fat body mitochondrial dysfunction and obesity phenotypes. Thus, perturbation of muscle mitochondrial activity regulates mitochondrial function in the fat body nonautonomously via modulation of Activin signaling.

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