Increased Fibro-Adipogenic Progenitors and Intramyocellular Lipid Accumulation in Obesity-Related Skeletal Muscle Dysfunction

Jia, Guanghong; Sowers,

doi:10.2337/dbi18-0047

Cited by 12 publications

(9 citation statements)

References 15 publications

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“…The muscle contains different progenitor cells, which include the myogenic progenitors, satellite cells, PW1+ progenitor cells, and fibro-adipogenic progenitor cells (FAPs) [1]. In the healthy skeletal muscle, a balance is maintained between these myogenic progenitors and the FAPs, and the FAPs are believed to aid in muscle regeneration [28,29]. Kozlowska et al showed that MSCs from the healthy skeletal muscles have the limited adipogenic potential [30], and Marinkovic et al showed that seeding purified skeletal muscle stem cells and FAPs in co-culture at a 1: 1 ratio inhibits lipid droplet formation even under adipogenic conditions [31].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture

et al. 2020

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Background: Mesenchymal stem/stromal cells (MSCs) can replenish the aged cells of the musculoskeletal system in adult life. Stem cell exhaustion and decrease in their regenerative potential have been suggested to be hallmarks of aging. Here, we investigated whether muscle-and bone-derived MSCs of patients with osteoarthritis and osteoporosis are affected by this exhaustion, compared to healthy donors. Methods: Patients with primary osteoarthritis, femoral neck fractures due to osteoporosis, and healthy donors (controls) were included. MSCs were isolated from the skeletal muscle and subchondral bone from each patient and compared using ex vivo and in vitro analyses, including immunophenotyping, colony-forming unit fibroblast assays, growth kinetics, cell senescence, multilineage potential, and MSC marker gene expression profiling. Results: Freshly isolated cells from muscle from patients with osteoarthritis showed a lower proportion of CD45/ CD19/CD14/CD34-negative cells compared to patients with osteoporosis and healthy donors. Freshly isolated muscle cells from patients with osteoarthritis and osteoporosis also showed higher clonogenicity compared to healthy donors. MSCs from both tissues of osteoarthritis patients showed significantly reduced osteogenesis and MSCs from the bone also reduced adipogenesis. Chondrogenic pellet diameter was reduced in bone-derived MSCs from both patient groups compared to healthy donors. A significant positive correlation was observed between adipogenesis and CD271 expression in muscle-derived MSCs. CD73 was significantly lower in bone-derived MSCs from osteoarthritis patients, compared to osteoporosis patients. Gene expression profiling showed significantly lower expression of MSC marker gene leptin receptor, LEPR, previously identified as the major source of the bone and adipocytes in the adult bone marrow, in bone-derived MSCs from patients with osteoarthritis in comparison with osteoporotic patients and healthy donors.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture

et al. 2020

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“…3), which means that the long-term unhealthy diet promoted the formation of autophagosomes, but blocked their degradation. Intramyocellular lipid content and ectopic fat storage, increased by excess lipid in skeletal muscle, had been proven to result in skeletal muscle dysfunction 27. Thus, the increased LC3II/LC3I ratio with HFHS diet may be an attempt to mitigate the associated metabolic result.…”

Section: Discussionmentioning

confidence: 99%

Effect of a Single Bout of Exercise on Autophagy Regulation in Skeletal Muscle of High-Fat High-Sucrose Diet-Fed Mice

Zhang

Lee

Kwak

et al. 2019

JOMES

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BackgroundAutophagy maintains metabolic homeostasis of muscles, and its impairment may cause muscle dysfunction. Exercise can improve muscle dysfunction induced by long-term high-fat diet. This study aimed to explore the association of autophagy with impaired muscle dysfunction in obese conditions and investigate its relationship with exercise-induced muscle function improvement.MethodsMale C57BL/6 mice (n=24) were randomly assigned to four groups: low-fat diet+plain water feeding sedentary (CON) group, low-fat diet+plain water feeding exercise (CON+EX) group, high-fat high-sucrose (HFHS) diet-fed sedentary group, and HFHS diet-fed exercise (HFHS+EX) group, and subjected to a single bout of exhaustive exercise.ResultsHFHS diet resulted in shorter hanging time, reduced grip force, and lower exhaustion time and distance, and decreased lean mass per body weight. Moreover, in the soleus, which is chosen as a representative red (oxidative) muscle, LC3II/LC3I ratio, P62, and Bnip3 levels were altered following the HFHS diet, and were negatively correlated with muscle performance parameters; exercise significantly decreased the LC3II/LC3 ratio while P62 increased with HFHS diet. Autophagy-related protein changes were not found in the white (glycolytic) gastrocnemius.ConclusionThe study revealed that 20-week HFHS diet causes a significant increase in body weight and fat mass, along with a decrease in muscle function. Autophagy-related LC3 and P62 protein expression was negatively correlated with muscle function, and they were reduced when a single bout of exercise stimulated the soleus of obese mice. However, no change of autophagy-related proteins was seen in the gastrocnemius.

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“…Several pan-PPAR agonists, including indeglitazar (EUCTR 2005-004227-19; NCT00425919), tetradecylthioacetic acid (NCT00605787), chiglitazar [74,75], and lanifibranor (NCT03459079) have been evaluated for T2DM. Clinical outcomes of most of these drugs are not accessible, but tetradecylthioacetic acid was discontinued due to impaired cardiac performance.…”

Section: Type 2 Diabetes Mellitus (T2dm)mentioning

confidence: 99%

“…The developmental status of indeglitazar is possibly halted, considering that the original developing company (Plexxikon) has been acquired by another pharmaceutical company (Daiichi Sankyo). An exception is chiglitazar which was recently revealed to be well-tolerated and more effective in lowering glycated hemoglobin A1c and restoring insulin sensitivity compared to placebo or sitagliptin based on two Phase III trial [74,75]. With chiglitazar and lanifibranor being active in T2DM clinical pipeline, the prospect of pan-PPAR agonists as antidiabetic agents remains optimistic.…”

Section: Type 2 Diabetes Mellitus (T2dm)mentioning

confidence: 99%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

167

152

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

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Increased Fibro-Adipogenic Progenitors and Intramyocellular Lipid Accumulation in Obesity-Related Skeletal Muscle Dysfunction

Cited by 12 publications

References 15 publications

Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture

Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture

Effect of a Single Bout of Exercise on Autophagy Regulation in Skeletal Muscle of High-Fat High-Sucrose Diet-Fed Mice

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

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