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

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.

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

2020 ◽  
Author(s):  
Hannah E. Wilson ◽  
David A. Stanton ◽  
Emidio E. Pistilli
Keyword(s):  
Breast Cancer ◽  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Lipid Accumulation ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Ppar Gamma ◽  
Independent Functions

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.

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

2004 ◽  
Vol 286 (3) ◽  
pp. E347-E353 ◽  
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.

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

2012 ◽  
Vol 302 (6) ◽  
pp. E731-E739 ◽  
Author(s):  
Maria H. Holmström ◽  
Eduardo Iglesias-Gutierrez ◽  
Juleen R. Zierath ◽  
Pablo M. Garcia-Roves
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Respiratory Capacity ◽  
Tissue Specific ◽  
Mitochondrial Respiratory

The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/ ?) and obese diabetic ( db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction.

scholarly journals A Pro12Ala polymorphism in the human peroxisome proliferator-activated receptor-gamma 2 is associated with combined hyperlipidaemia in obesity

2001 ◽  
pp. 277-282 ◽  
Author(s):  
MM Swarbrick ◽  
CM Chapman ◽  
BM McQuillan ◽  
J Hung ◽  
PL Thompson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Target Genes ◽  
Venous Blood ◽  
Density Lipoprotein ◽  
Ppar Gamma ◽  
Disease Assessment ◽  
Peroxisome Proliferator ◽  
Pro12ala Polymorphism ◽  
Peroxisome Proliferator Activated Receptor ◽  
Significant Difference

OBJECTIVE: Peroxisome proliferator-activated receptor-gamma 2 (PPAR gamma 2) is an important regulator of adipose tissue metabolism and insulin sensitivity. The aim of this investigation was to determine whether a PPAR gamma 2 Pro12Ala polymorphism was associated with cardiovascular risk factors (obesity, blood pressure, diabetes and blood lipids) in Western Australian Caucasians (n=663). DESIGN: Subjects were selected from two population studies (the Carotid Ultrasound Disease Assessment Study (CUDAS) and Busselton Population Health Survey) on the basis of body mass index (BMI). 292 obese (BMI > or =30 kg/m) and 371 lean (BMI <25 kg /m) subjects were studied. METHODS: Blood pressure and anthropometric measurements were collected from all participants, as well as a fasting venous blood sample. Biochemical measurements (high-density lipoprotein (HDL)- and low-density lipoprotein-cholesterol, triglycerides) and PPAR gamma 2 Pro12Ala genotype were also determined. RESULTS: Obese Pro/Ala and Ala/Ala subjects had lower levels of HDL-cholesterol (P=0.032) and a trend towards higher levels of triglycerides (P=0.055) compared with obese Pro/Pro subjects. In the obese group, the Ala allele was significantly associated with the presence of combined hyperlipidaemia (odds ratio = 2.33, P=0.042). There was no significant difference in the frequency of the polymorphism between lean and obese groups (P=0.069). No association was observed between Pro12Ala genotype and obesity, blood pressure or diabetes in either group. CONCLUSIONS: Obese carriers of the Pro12Ala polymorphism have a greater risk of developing combined hyperlipidaemia, possibly due to impaired activation of PPAR gamma target genes. The Pro12Ala polymorphism is not directly associated with obesity, hypertension or diabetes in this population.

SUMO modification selectively regulates transcriptional activity of peroxisome-proliferator-activated receptor γ in C2C12 myotubes

2010 ◽  
Vol 433 (1) ◽  
pp. 155-161 ◽  
Author(s):  
Sung Soo Chung ◽  
Byung Yong Ahn ◽  
Min Kim ◽  
Jun Ho Kho ◽  
Hye Seung Jung ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Transcriptional Activity ◽  
Target Genes ◽  
C2c12 Cells ◽  
C2c12 Myotubes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mouse Muscle ◽  
Fatty Acid Binding ◽  
Specific Protease

PPAR (peroxisome-proliferator-activated receptor) γ, a nuclear receptor, can be conjugated with SUMO (small ubiquitin-like modifier), which results in the negative regulation of its transcriptional activity. In the present study, we tested whether de-SUMOylation of PPARγ affects the expression of PPARγ target genes in mouse muscle cells and investigated the mechanism by which de-SUMOylation increases PPARγ transcriptional activity. We found that the SUMO-specific protease SENP2 [SUMO1/sentrin/SMT3 (suppressor of mif two 3 homologue 1)-specific peptidase 2] effectively de-SUMOylates PPARγ–SUMO conjugates. Overexpression of SENP2 in C2C12 cells increased the expression of some PPARγ target genes, such as FABP3 (fatty-acid-binding protein 3) and CD36 (fatty acid translocase), both in the absence and presence of rosiglitazone. In contrast, overexpression of SENP2 did not affect the expression of another PPARγ target gene ADRP (adipose differentiation-related protein). De-SUMOylation of PPARγ increased ChIP (chromatin immunoprecipitation) of both a recombinant PPRE (PPAR-response element) and endogenous PPREs of the target genes CD36 and FABP3, but ChIP of the PPRE in the ADRP promoter was not affected by SENP2 overexpression. In conclusion, these results indicate that SENP2 de-SUMOylates PPARγ in myotubes, and de-SUMOylation of PPARγ selectively increases the expression of some PPARγ target genes.

scholarly journals Mulberry (Morus alba L.) Fruit Extract Ameliorates Inflammation via Regulating MicroRNA-21/132/143 Expression and Increases the Skeletal Muscle Mitochondrial Content and AMPK/SIRT Activities

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1453
Author(s):  
Sunyoon Jung ◽  
Mak-Soon Lee ◽  
Eugene Chang ◽  
Chong-Tai Kim ◽  
Yangha Kim
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Inflammatory Cytokine ◽  
Uncoupling Protein ◽  
Morus Alba ◽  
Macrophage Infiltration ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Fruit Extract

The Mulberry (Morus alba L.) fruit is a rich source of polyphenolic compounds; most of these are anthocyanins. Obesity is intimately related to low-grade inflammation, with increased pro-inflammatory cytokine secretion and macrophage infiltration in white adipose tissue (WAT). This study investigated whether mulberry fruit extract (ME) has beneficial effects on obesity-induced inflammation and skeletal muscle mitochondrial dysfunction. Sprague-Dawley rats were divided into four groups and fed either a low-fat diet (LFD), high-fat diet (HFD), HFD + 5 g/kg of ME (ME-L), or HFD + 10 g/kg of ME (ME-H) for 14 weeks. ME alleviated dyslipidemia and lipid accumulation, as well as pro-inflammatory cytokine production such as tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and monocyte chemoattractant protein 1 (MCP1) in the WAT. ME mitigated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and macrophage infiltration in WAT. Notably, microRNA (miR)-21, miR-132, and miR-43 expressions were downregulated in the WAT of the ME groups compared to the HFD group. Moreover, ME increased the mitochondrial size and mitochondrial DNA (mtDNA) content, as well as key genes’ expression related to mitochondrial function, including sirtuin (SIRT)1, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), carnitine palmitoyltransferase 1β (CPT-1β), and uncoupling protein 3 (UCP3), and adenosine monophosphate-activated protein kinase (AMPK)/SIRT activities in skeletal muscle. These results suggested that ME might alleviate obesity-induced inflammation and mitochondrial dysfunction by regulating miR-21, miR-132, and miR-43 expression in WAT, and by activating the PGC-1α/SIRT1 pathway in muscle.

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

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.

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

2020 ◽  
Vol 15 (7) ◽  
pp. 926-936 ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document