Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Gumucio, Jonathan P.; Qasawa, Austin H.; Ferrara, Patrick J.; Malik, Afshan N.; Funai, Katsuhiko; Mendias, Christopher L.

doi:10.1096/fj.201802457rr

Cited by 75 publications

(68 citation statements)

References 80 publications

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“…Changes in the metabolome and lipidome have important functional consequences in the context of rotator cuff tears. Using a rat model, we demonstrated that mitochondrial dysfunction leads to the progressive lipid accumulation that occurs after rotator cuff tear . We did not directly measure mitochondrial function in the current study, but gene enrichment analysis predicted mitochondrial dysfunction in both B6 and MRL groups after rotator cuff tear, and there was a downregulation in key genes involved in β‐oxidation of lipids in mitochondria and aerobic metabolism.…”

Section: Discussionmentioning

confidence: 81%

“…However, while MRL mice had higher sF o values, both strains experienced a 40% reduction in sF o after tear. Using the same surgical model, rats had a 50% reduction in sF o 30 days after rotator cuff tear . Patients with a rotator cuff tear have a 29% reduction in sF o , and sF o is negatively correlated with patient‐reported indices of shoulder function .…”

Section: Discussionmentioning

confidence: 99%

“…Mice were anesthetized with 2% isoflurane, and a bilateral, full‐thickness supraspinatus and infraspinatus tenectomy and denervation was performed . A deltoid‐splitting transacromial approach exposed the supraspinatus and infraspinatus tendons, which were then finely detached from their humeral footprint.…”

Section: Methodsmentioning

confidence: 99%

“…RNA was isolated from muscles, and gene expression and RNAseq was performed as described . The samples were homogenized in QIAzol (Qiagen, Valencia, CA) and RNA was isolated using 5PRIME Phase Lock Gel tubes (Quantabio, Beverly, MA), an RNeasy Mini kit (Qiagen), and DNase I (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…Mass spectrometry‐based metabolomics and lipidomics was performed by the University of Michigan Metabolomics Core as described . The summary data is provided in the manuscript, with complete data available in Supplementary Tables S1 and S2.…”

Section: Methodsmentioning

confidence: 99%

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The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear

Talarek

Piacentini

Konja

et al. 2019

Journal Orthopaedic Research

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Chronic rotator cuff tears are a common source of shoulder pain and disability. Patients with rotator cuff tears often have substantial weakness, fibrosis, and fat accumulation, which limit successful surgical repair and postoperative rehabilitation. The Murphy Roths Large (MRL) strain of mice have demonstrated superior healing and protection against pathological changes in several disease and injury conditions. We tested the hypothesis that, compared with the commonly used C57Bl/6 (B6) strain, MRL mice would have less muscle fiber atrophy and fat accumulation, and be protected against the loss in force production that occurs after cuff tear. Adult male B6 and MRL mice were subjected to a rotator cuff tear, and changes in muscle fiber contractility and histology were measured. RNA sequencing and shotgun metabolomics and lipidomics were also performed. The muscles were harvested one month after tear. B6 and MRL mice had a 40% reduction in relative muscle force production after rotator cuff tear. RNA sequencing identified an increase in fibrosis‐associated genes and a reduction in mitochondrial metabolism genes. The markers of glycolytic metabolism increased in B6 mice, while MRL mice appeared to increase amino acid metabolism after tear. There was an accumulation of lipid after injury, although there was a divergent response between B6 and MRL mice in the types of lipid species that accrued. There were strain‐specific differences between the transcriptome, metabolome, and lipidome of B6 and MRL mice, but these differences did not protect MRL mice from weakness and pathological changes after rotator cuff tear. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:811‐822, 2020

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear

Talarek

Piacentini

Konja

et al. 2019

Journal Orthopaedic Research

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The mediation roles of intermuscular fat and inflammation in muscle mitochondrial associations with cognition and mobility

Tian,

Lee,

Yang

et al. 2023

J cachexia sarcopenia muscle

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BackgroundMitochondrial dysfunction may contribute to brain and muscle health through inflammation or fat infiltration in the muscle, both of which are associated with cognitive function and mobility. We aimed to examine the association between skeletal muscle mitochondrial function and cognitive and mobility outcomes and tested the mediation effect of inflammation or fat infiltration.MethodsWe analysed data from 596 Baltimore Longitudinal Study of Aging participants who had concurrent data on skeletal muscle oxidative capacity and cognitive and mobility measures of interest (mean age: 66.1, 55% women, 24% Black). Skeletal muscle oxidative capacity was assessed as post‐exercise recovery rate (kPCr) via P31 MR spectroscopy. Fat infiltration was measured as intermuscular fat (IMF) via CT scan and was available for 541 participants. Inflammation markers [IL‐6, C‐reactive protein (CRP), total white blood cell (WBC), neutrophil count, erythrocyte sedimentation rate (ESR), or albumin] were available in 594 participants. We examined the association of kPCr and cognitive and mobility measures using linear regression and tested the mediation effect of IMF or inflammation using the mediation package in R. Models were adjusted for demographics and PCr depletion.ResultskPCr and IMF were both significantly associated with specific cognitive domains (DSST, TMA‐A, and pegboard dominant hand performance) and mobility (usual gait speed, HABCPPB, 400 m walk time) (all P < 0.05). IMF significantly mediated the relationship between kPCr and these cognitive and mobility measures (all P < 0.05, proportion mediated 13.1% to 27%). Total WBC, neutrophil count, and ESR, but not IL‐6 or CRP, also mediated at least one of the cognitive and mobility outcomes (all P < 0.05, proportion mediated 9.4% to 15.3%).ConclusionsSkeletal muscle mitochondrial function is associated with cognitive performance involving psychomotor speed. Muscle fat infiltration and specific inflammation markers mediate the relationship between muscle mitochondrial function and cognitive and mobility outcomes. Future studies are needed to confirm these associations longitudinally and to understand their mechanistic underpinnings.

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RORα–GABP–TFAM axis alleviates myosteatosis with fatty atrophy through reinforcement of mitochondrial capacity

Kim,

Lee,

Jeong

et al. 2024

J cachexia sarcopenia muscle

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BackgroundFat infiltration in muscle, called ‘myosteatosis’, precedes muscle atrophy, which subsequently results in sarcopenia. Myosteatosis is frequently observed in patients with nonalcoholic fatty liver disease (NAFLD). We have previously reported that retinoic acid receptor‐related orphan receptor‐α (RORα) regulates mitochondrial dynamics and mitophagy in hepatocytes, resulting in an alleviation of NAFLD. In this study, we aimed to investigate the role of RORα in skeletal muscle and to understand molecular mechanisms by which RORα controls mitochondrial capacity, using an NAFLD‐associated myosteatosis mouse model.MethodsTo establish a myosteatosis model, 7‐week‐old C57BL/6N mice were fed with high‐fat diet (HFD). After 15 weeks of diet feeding, an adeno‐associated virus vector encoding RORα (AAV‐RORα) was injected to gastrocnemius (GA) muscles, or after 7 weeks of HFD feeding, JC1‐40, an RORα agonistic ligand, was administered daily at a dose of 5 mg/kg/day by oral gavage for 5 weeks. Histological, biochemical and molecular analyses in various in vivo and in vitro experiments were performed.ResultsFirst, the number of oxidative MyHC2a fibres with intensive lipid infiltration increased by 3.8‐fold in the red region of the GA of mice with myosteatosis (P < 0.001). RORα was expressed around MyHC2a fibres, and its level increased by 2.7‐fold after HFD feeding (P < 0.01). Second, treatment of RORα ligands in C2C12 myoblasts, such as cholesterol sulfate and JC1‐40, enhanced the number of oxidative fibres stained for MyHC1 and MyHC2a by two‐fold to four‐fold (P < 0.01), while it reduced the lipid levels in MyHC2a fibres by 20–50% (P < 0.001) in the presence of palmitic acids. Third, mitochondrial membrane potential (P < 0.01) and total area of mitochondria (P < 0.01) were enhanced by treatment of these ligands. Chromatin immunoprecipitation analysis showed that RORα bound the promoter of GA‐binding protein α subunit gene that led to activation of mitochondrial transcription factor A (TFAM) in C2C12 myoblasts (P < 0.05). Finally, intramuscular transduction of AAV‐RORα alleviated the HFD‐induced myosteatosis with fatty atrophy; lipid contents in MyHC2a fibres decreased by 48% (P < 0.001), whereas the number of MyHC2b fibre increased by 22% (P < 0.001). Also, administration of JC1‐40 improved the signs of myosteatosis in that it decreased the level of adipose differentiation‐related protein (P < 0.01) but increased mitochondrial proteins such as cytochrome c oxidase 4 and TFAM in GA muscle (P < 0.01).ConclusionsRORα plays a versatile role in regulating the quantity of mitochondria and the oxidative capacity, ultimately leading to an improvement in myosteatosis symptoms.

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Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Cited by 75 publications

References 80 publications

The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear

The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear

The mediation roles of intermuscular fat and inflammation in muscle mitochondrial associations with cognition and mobility

RORα–GABP–TFAM axis alleviates myosteatosis with fatty atrophy through reinforcement of mitochondrial capacity

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