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Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.
Cardaci, Thomas D; VanderVeen, Brandon N; Huss, Alexander R; Bullard, Brooke M; Velázquez, Kandy T; Frizzell, Norma; Carson, James A; Price, Robert L; Murphy, E Angela.
Afiliação
  • Cardaci TD; Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States.
  • VanderVeen BN; Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States.
  • Huss AR; Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States.
  • Bullard BM; Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States.
  • Velázquez KT; Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States.
  • Frizzell N; Columbia Department of Veterans Affairs Health Care System, Columbia, South Carolina, United States.
  • Carson JA; Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, United States.
  • Price RL; Department of Kinesiology and Sports Management, JL Huffines Institute for Sports Medicine & Human Performance, Texas A&M University, College Station, Texas, United States.
  • Murphy EA; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, United States.
Am J Physiol Cell Physiol ; 327(3): C684-C697, 2024 Sep 01.
Article em En | MEDLINE | ID: mdl-39010842
ABSTRACT
Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. Although its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular lipid droplet (LD) content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis lung carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n = 20) were implanted with LLC cells (106) in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red O/lipid staining [tibialis anterior (TA)], and protein (gastrocnemius). LLC mice had a greater number (232%; P = 0.006) and size (130%; P = 0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; P = 0.0109) and "very high" oil-red O positive (178%; P = 0.0002) fibers compared with controls and this was inversely correlated with fiber size (R2 = 0.5294; P < 0.0001). Morphological analyses of LDs show increased elongation and complexity [aspect ratio intermyofibrillar (IMF) = 9%, P = 0.046) with decreases in circularity [circularity subsarcolemmal (SS) = 6%, P = 0.042] or roundness (roundness whole = 10%, P = 0.033; IMF = 8%, P = 0.038) as well as decreased LD-mitochondria touch (-15%; P = 0.006), contact length (-38%; P = 0.036), and relative contact (86%; P = 0.004). Furthermore, dysregulation in lipid metabolism (adiponectin, CPT1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (P < 0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.NEW & NOTEWORTHY We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Caquexia / Músculo Esquelético / Carcinoma Pulmonar de Lewis / Gotículas Lipídicas / Camundongos Endogâmicos C57BL Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Caquexia / Músculo Esquelético / Carcinoma Pulmonar de Lewis / Gotículas Lipídicas / Camundongos Endogâmicos C57BL Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article