Disrupted macrophage metabolic reprogramming in aged soleus muscle during early recovery following disuse atrophy

Fix, Dennis K.; Ekiz, H. Atakan; Petrocelli, Jonathan J; Mckenzie, Alec M.; Mahmassani, Ziad; O’Connell, Ryan M.; Drummond, Micah J.

doi:10.1111/acel.13448

Cited by 15 publications

(10 citation statements)

References 49 publications

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“…Peritoneal macrophages have previously been assessed for phagocytosis activity after polarisation with M1-like or M2-like stimuli with comparable phagocytic activity between young and old following M2 polarisation but a reduction in phagocytosis with age in M1-like macrophages, similar to our findings (39). Fix et al, also found an impairment in phagocytosis with age in pro-inflammatory BMDMs (16). In contrast to our findings in human MDMs, IFN/LPS stimulation has been found to increase phagocytosis in both young and old BMDMs compared with M 0 (17).…”

Section: Discussionmentioning

confidence: 93%

“…Similarly, alveolar macrophages consistently show a reduction in phagocytic activity with age, including lower phagocytosis of apoptotic neutrophils (14) and E. coli (15). However, aged mouse bone marrow-derived macrophages (BMDM) showed no defect in uptake of zymosan particles (10), fluorescent particles (8), latex particles (16), or E. coli (17). In contrast, decreased phagocytosis with age was seen for uptake of apoptotic Jurkat cells (18), myelin fragments (9) and apoptotic N2A cell debris or E. coli bioparticles (19).…”

Section: Introductionmentioning

confidence: 99%

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Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes

Moss,

Johnston,

Clements

et al. 2023

Preprint

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Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related immunity changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration and chemotaxis in human monocyte-derived macrophages (MDMs) from older (>50 years) compared with younger (18-30 years) donors, alongside downregulation of transcription factors MYC and USF1 with age. In MDMs from young donors, knockdown of MYC or USF1 decreased phagocytosis and chemotaxis and altered expression of genes associated with these functions, as well as adhesion and extracellular matrix remodelling. A concordant dysregulation of MYC and USF1 target genes was also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs led to an increased cell size, altered morphology and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in ageing.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes

Moss,

Johnston,

Clements

et al. 2023

Preprint

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“…In coordination with macrophages, FAPs play an essential role in the proper remodeling of skeletal muscle following injury (Abramowitz et al, 2018) yet are functionally impaired with aging (Fix et al, 2021; Lukjanenko et al, 2019; Reidy et al, 2019; Schuler et al, 2021). While the necessity of FAPs for full resolution from muscle injury is well understood (Murphy et al, 2011), less is known about FAP senescence in muscle repair and remodeling after disuse, especially in aged adults.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the importance of macrophages in muscle remodeling is well understood as the absence of macrophages corresponds with muscle fibrosis and impaired muscle recovery (Arnold et al, 2007; Martinez et al, 2010; Ochoa et al, 2007) while in humans, muscle macrophage content positively correlates with muscle size after exercise training (Walton et al, 2019). Interventional therapy such as metformin is particularly relevant in this context since macrophage and FAP function are disrupted during recovery in aging (Fix et al, 2021; Lukjanenko et al, 2019; Reidy et al, 2019; Schuler et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Disuse‐induced muscle fibrosis, cellular senescence, and senescence‐associated secretory phenotype in older adults are alleviated during re‐ambulation with metformin pre‐treatment

et al. 2023

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Muscle inflammation and fibrosis underlie disuse‐related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re‐ambulation period. A two‐arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two‐week run‐in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin‐treated individuals had less type‐I myofiber atrophy during disuse, reduced pro‐inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro‐adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast‐like. Together, these results suggest that metformin pre‐treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.

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“…HIF-1α induces the binding of GLUT1, which controls glucose transport, and related genes during glycolysis by forming a dimer with HIF-1β and the intranuclear hypoxia response element on the target gene (54). In aging skeletal muscle, HIF-1α downregulation inhibits its downstream GLUT1, affecting macrophage glycolysis, thereby inhibiting its M1 polarization and phagocytosis (55). In addition, the drug silver forgesine degrades the proteasome of HIF-1α by affecting the expression of GLUT1, PKM, PDK1, lactate dehydrogenase (LDH)A and PFK, which further inhibits macrophage glycolysis, thereby limiting their polarization to the M1 type (56).…”

Section: Effect Of Metabolic Reprogramming Of Tams On Their Polarizat...mentioning

confidence: 99%

Effects of glycolysis on the polarization and function of tumor‑associated macrophages (Review)

et al. 2023

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Under conditions of oxygen sufficiency, tumor cells supply themselves with energy through glycolysis, which is one of the causes of their rapid proliferation, metastasis and acquisition of drug resistance. Tumor-associated macrophages (TAMs) are transformed from peripheral blood monocytes and are among the immune-related cells that constitute the tumor microenvironment (TME). Altered glycolysis levels in TAMs have an important impact on their polarization and function. The cytokines secreted by TAMs, and phagocytosis in different polarization states, affect tumorigenesis and development. Furthermore, changes in glycolysis activity of tumor cells and other immune-related cells in the TME also affect the polarization and function of TAMs. Studies on the relationship between glycolysis and TAMs have received increasing attention. The present study summarized the link between glycolysis of TAMs and their polarization and function, as well as the interaction between changes in glycolysis of tumor cells and other immune-associated cells in the TME and TAMs. The present review aimed to provide a comprehensive understanding of the effects of glycolysis on the polarization and function of TAMs. Contents 1. Introduction 2. Effects of altered glycolysis of TAMs on their own polarization and function 3. Effects of altered levels of glycolysis in tumor cells and other immune cells in the TME on TAM polarization and function 4. Problems and perspectives

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Disrupted macrophage metabolic reprogramming in aged soleus muscle during early recovery following disuse atrophy

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 15 publications

References 49 publications

Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes

Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes

Disuse‐induced muscle fibrosis, cellular senescence, and senescence‐associated secretory phenotype in older adults are alleviated during re‐ambulation with metformin pre‐treatment

Effects of glycolysis on the polarization and function of tumor‑associated macrophages (Review)

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