Adipose triglyceride lipase decrement affects skeletal muscle homeostasis during aging through FAs-PPARα-PGC-1α antioxidant response

Aquilano, Katia; Baldelli, Sara; Barbera, Livia La; Barbato, Daniele Lettieri; Tatulli, Giuseppe; Ciriolo, Maria Rosa

doi:10.18632/oncotarget.8552

Cited by 30 publications

(48 citation statements)

References 52 publications

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“…RNA (3 μg) was retro-transcripted by using M-MLV (Promega, Madison, WI). qPCR was performed in triplicate by using validated qPCR primers (BLAST), Applied Biosystems™ Power™ SYBR™ Green Master Mix, and the QuantStudio3 Real-Time PCR System (Thermo Fisher, Whaltam, MA, USA) as previously described 75 . mRNA levels were normalized to actin mRNA, and the relative mRNA levels were determined through the 2 −ΔΔCt method.…”

Section: Real-time Pcrmentioning

confidence: 99%

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

et al. 2020

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Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and antidiabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.

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Section: Real-time Pcrmentioning

confidence: 99%

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

et al. 2020

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“…A recent study reported the decline of ATGL with age in the murine gastrocnemius muscle (46). However, we did not find significant decrease in the ATGL protein or mRNA levels with age in the white gastrocnemius muscle, which could be attributed to the different genetic background and the difference in the age group of rodents used for both the studies.…”

Section: Discussionmentioning

confidence: 99%

PPARa‐ATGL pathway improves muscle mitochondrial metabolism: implication in aging

et al. 2016

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Adipose triglyceride lipase (ATGL) maintains an optimum mitochondrial function putatively by generating cognate ligands for peroxisome proliferator-activated receptor α (PPARα), which, together with PPARγ coactivator-1α (PGC1α), regulate muscle mitochondrial biogenesis. However, the cross-talk between ATGL and PPARα in skeletal muscle mitochondrial metabolism and its implication in chronological aging is poorly understood. The role of ATGL in muscle mitochondrial metabolism was studied by overexpressing and depleting the gene and studying its downstream effect in cultured myotubes and in murine skeletal muscle. We found that PPARα directly induces ATGL expression during myogenesis. Overexpression of ATGL significantly enhanced while depletion of ATGL attenuated mitochondrial oxidative phosphorylation and fatty acid oxidation without alteration in mitochondrial content, and it rendered PPARα and PGC1α redundant in promoting mitochondrial oxidative function. However, ATGL did not alter PPARα-dependent lipid accumulation and insulin sensitivity. In middle-aged rats, ATGL expression was higher and correlated with PPARα expression and sustained fatty acid oxidation in oxidative soleus muscle. Fenofibrate feeding further induced ATGL expression selectively in this muscle compartment. These findings illustrate that PPARα and ATGL constitute a regulatory pathway in skeletal muscle, suggesting their role as a mitochondrial metabolic reserve.-Biswas, D., Ghosh, M., Kumar, S., Chakrabarti, P. PPARα-ATGL pathway improves muscle mitochondrial metabolism: implication in aging.

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“…In addition, also, resistin has been shown to promote IMCL storage in primary human myotubes . Importantly, increased IMCL storage results in the accumulation and dysregulation of detrimental lipid intermediates such as diacylglycerols (DAGs) and ceramides, and those intermediates lead to insulin resistance through activation of protein kinase C (PKC) . High levels of DAG and ceramides have also been suggested to play a role in the development of muscle loss .…”

Section: Determinants Of Muscle Massmentioning

confidence: 99%

“…71 Importantly, increased IMCL storage results in the accumulation and dysregulation of detrimental lipid intermediates such as diacylglycerols (DAGs) and ceramides, and those intermediates lead to insulin resistance through activation of protein kinase C (PKC). [90][91][92][93][94][95][96][97][98][99][100] High levels of DAG and ceramides have also been suggested to play a role in the development of muscle loss. 16, [101][102][103] In C2C12 and L6 myotubes, treatment with the fatty acid palmitate induced ceramide accumulation, and this was associated with increased expression of pro-atrophic genes such as atrogin-1/MAFbx, increased levels of FoxO3, upregulated eIF2α phosphorylation, and decreased protein synthesis.…”

Section: Lipid Accumulation In Skeletal Musclementioning

confidence: 99%

Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes

2019

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Summary Insulin resistance and muscle mass loss often coincide in individuals with type 2 diabetes. Most patients with type 2 diabetes are overweight, and it is well established that obesity and derangements in lipid metabolism play an important role in the development of insulin resistance in these individuals. Specifically, increased adipose tissue mass and dysfunctional adipose tissue lead to systemic lipid overflow and to low‐grade inflammation via altered secretion of adipokines and cytokines. Furthermore, an increased flux of fatty acids from the adipose tissue may contribute to increased fat storage in the liver and in skeletal muscle, resulting in an altered secretion of hepatokines, mitochondrial dysfunction, and impaired insulin signalling in skeletal muscle. Recent studies suggest that obesity and lipid derangements in adipose tissue can also lead to the development of muscle atrophy, which would make insulin resistance and muscle atrophy two sides of the same coin. Unfortunately, the exact relationship between lipid accumulation, type 2 diabetes, and muscle atrophy remains largely unexplored. The aim of this review is to discuss the relationship between type 2 diabetes and muscle loss and to discuss some of the joint pathways through which lipid accumulation in organs may affect peripheral insulin sensitivity and muscle mass.

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Adipose triglyceride lipase decrement affects skeletal muscle homeostasis during aging through FAs-PPARα-PGC-1α antioxidant response

Cited by 30 publications

References 52 publications

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

PPARa‐ATGL pathway improves muscle mitochondrial metabolism: implication in aging

Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes

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