Lipotoxicity, aging, and muscle contractility: does fiber type matter?

Carter, Christy S.; Justice, Jamie N.; Thompson, LaDora V.

doi:10.1007/s11357-019-00077-z

Cited by 42 publications

(41 citation statements)

References 88 publications

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“…The rapid SM energetic decline is associated with significantly reduced mitochondrial oxidative capacity and markedly increased muscle fat accumulation. Although our data do not answer the question of whether mitochondrial abnormalities cause fatty accumulation or vice versa, they suggest that fatty replacement of SM and the previously described proinflammatory state ( 50 ) contribute to impaired SM HEP metabolism possibly through paracrine effects ( 51 – 53 ) and, in turn, increased fatigability in age-related frailty.…”

Section: Discussioncontrasting

confidence: 87%

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

Lewsey¹,

Weiss²,

Schär³

et al. 2020

JCI Insight

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BACKGROUND Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown. METHODS Here, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31 P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO 2 ). RESULTS During graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31 P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing ( P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI. CONCLUSION Several-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations. FUNDING This work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.

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Section: Discussioncontrasting

confidence: 87%

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

Lewsey¹,

Weiss²,

Schär³

et al. 2020

JCI Insight

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“…Aberrant cell signaling pathways in cancer are common. Activation and mutations of PI3 kinase (PI3K), mTOR, insulin-like growth factor (IGF-1), epidermal growth factor receptor (EGFR), and NF-kB pathways have all been identified in several human disorders (Lewis et al, 2018;Souder and Anderson, 2019;Carter et al, 2019;Farias Quipildor et al, 2019), especially cancer (Hanahan and Weinberg, 2011;Royce et al, 2019). IGF-1 is a ligand for receptor tyrosine kinases Abbreviations: ATCC, American Type Tissue Culture; BLI, bioluminescence intensity; BDNF, brain derived neurotrophic factor; DAPI, 4′,6-diamidino-2phenylindole; DMSO, Dimethyl sulfoxide; ELISA, enzyme-linked immunoabsorbent assay; GBM, glioblastoma multiforme; GSC, glioma stem cell; IP, intraperitoneal; OS, overall survival; PI3K/mTOR, phosphoinositide 3-kinase/ mammalian target of rapamycin; PO, per os, by mouth; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; VM, vasculogenic mimicry; NF-kB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; JNK, c-Jun N-terminal kinase; STAT3, Signal transducer and activator of transcription 3.…”

Section: Introductionmentioning

confidence: 99%

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

et al. 2020

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Glioblastoma multiform (GBM) is the most common primary glial tumor resulting in very low patient survival despite current extensive therapeutic efforts. Emerging evidence suggests that more effective treatments are required to overcome tumor heterogeneity, drug resistance and a complex tumor-supporting microenvironment. PBI-05204 is a specifically formulated botanical drug consisting of a modified supercritical C0 2 extract of Nerium oleander that has undergone both phase I and phase II clinical trials in the United States for treatment of patients with a variety of advanced cancers. The present study was designed to investigate the antitumor efficacy of this botanical drug against glioblastoma using both in vitro and in vivo cancer models as well as exploring efficacy against glioblastoma stem cells. All three human GBM cell lines, U87MG, U251, and T98G, were inhibited by PBI-05204 in a concentration dependent manner that was characterized by induction of apoptosis as evidenced by increased ANNEXIN V staining and caspase activities. The expression of proteins associated with both Akt and mTOR pathway was suppressed by PBI-05240 in all treated human GBM cell lines. PBI-05204 significantly suppressed U87 spheroid formation and the expression of important stem cell markers such as SOX2, CD44, and CXCR4. Oral administration of PBI-05204 resulted in a dosedependent inhibition of U87MG, U251, and T98G xenograft growth. Additionally, PBI-05204-treated mice carrying U87-Luc cells as an orthotropic model exhibited significantly

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“…Gain of fat mass is significantly and independently associated with declining physical performance as well as an increased risk for disability, hospitalizations, and mortality in older individuals. This increased fat mass is not exclusively stored in adipose depots but may become deposited in non-adipose tissues [27]. Our study found that a significant weight gain (Fig.…”

Section: Effects Of Efandllf On Body Weight Blood Lipids and Liver Funmentioning

confidence: 47%

Systemic osteoprotective effects of Epimedii Folium and Ligustri Lucidi Fructus in senile osteoporosis rats by promoting the osteoblastogenesis and osteoclastogenesis based on MLP-ANN model

Tang

Yingying

et al. 2020

Chin Med

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Background: Senile osteoporosis (SOP), which is caused by unbalanced bone remodeling, leads to significant economic and societal burdens globally. The combination of Epimedii Folium (EF) and Ligustri Lucidi Fructus (LLF) serves as a commonly-used prescription for SOP in Traditional Chinese Medicine (TCM). This study aimed to evaluate the osteoprotective effects of EF and LLF in combination on SOP rats based on the constructed multilayer perception (MLP)-artificial neural network (ANN) model. Methods: 15 month old male Sprague-Dawley rats were administrated with EF, LLF or the combination of EF and LLF (EF&LLF) for 2 months, while 17 month old rats were used as the aging control group. All the rats were anesthetized with 25% ethyl carbamate, then their serum liver and bone tissues were taken. We detected bone mass, bone mineral density (BMD), biomechanics and the microstructure of bone trabecula by micro-CT and H&E staining to evaluate the degree of osteoporosis. Blood lipids and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT) and liver pathology were use to assess the side effects of drugs. Levels of alkaline phosphatase (ALP) and Tartrate-resistant acid phosphatase (TRACP) and the ratio of ALP to TRACP both in serum and bone were measured for the evaluation of bone turnover rate. The bone mRNA and protein expression of osteoprotegerin (OPG), nuclear factor-kappa B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), d2 isoform of vacuolar (H +) ATPase (ATP6V0d2), insulin-like growth factor (IGF-1), bone morphogenetic protein-2 (BMP2), M-CSF, Wnt5a, transforming growth factor-β1 (TGF-β1) were detected for evaluating bone metabolism. Results: The results showed that EF&LLF improved bone mass and bone quality by preventing bone loss, increasing maximal load as well as protecting the micro-structural retrogressive change of trabecular bone in SOP rats; ameliorated the steatosis in the liver and decreased blood lipids and serum ALT, AST and GGT; enhanced bone remodeling by stimulating the expression of ALP and TRACP. At the molecular levels, EF&LLF stimulated the osteoclastogenesis by upregulating the protein and mRNA expression of OPG, RANKL, M-CSF and ATP6V0d2; meanwhile, EF&LLF stimulated

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Lipotoxicity, aging, and muscle contractility: does fiber type matter?

Cited by 42 publications

References 88 publications

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

Systemic osteoprotective effects of Epimedii Folium and Ligustri Lucidi Fructus in senile osteoporosis rats by promoting the osteoblastogenesis and osteoclastogenesis based on MLP-ANN model

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