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  • 1
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    Online Resource
    Pharmacological inhibition of TLR4 ameliorates muscle and liver ceramide content after disuse in previously physically active mice
    American Physiological Society ; 2020
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 318, No. 3 ( 2020-03-01), p. R503-R511
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 318, No. 3 ( 2020-03-01), p. R503-R511
    Abstract: Toll-like receptor 4 (TLR4) is a proposed mediator of ceramide accumulation, muscle atrophy, and insulin resistance in skeletal muscle. It is currently unknown whether pharmacological inhibition of TLR4, using the TLR4-specific inhibitor TAK-242 during muscle disuse, is able to prevent changes in intracellular ceramide species and consequently preserve muscle size and insulin sensitivity in physically active mice. To address this question, we subjected running wheel-conditioned C57BL/6 male mice (13 wk old; ∼10/group) to 7 days of hindlimb suspension (HS), 7 days of continued wheel running (WR), or daily injections of TAK-242 during HS (HS + TAK242) for 7 days. We measured hindlimb muscle morphology, intramuscular and liver ceramide content, HOMA-IR, mRNA proxies of ceramide turnover and lipid trafficking, and muscle fatty acid and glycerolipid content. As a result, soleus and liver ceramide abundance was greater ( P 〈 0.05) in HS vs. WR but was reduced with TLR4 inhibition (HS + TAK-242 vs. HS). Muscle mass declined ( P 〈 0.01) with HS (vs. WR), but TLR4 inhibition did not prevent this loss (soleus: P = 0.08; HS vs. HS + TAK-242). HOMA-IR was impaired ( P 〈 0.01) in HS versus WR mice, but only fasting blood glucose was reduced with TLR4 inhibition (HS + TAK-242 vs HS, P 〈 0.05). Robust decreases in muscle Spt2 and Cd36 mRNA and muscle lipidomic trafficking may partially explain reductions in ceramides with TLR4 inhibition. In conclusion, pharmacological TLR4 inhibition in wheel-conditioned mice prevented ceramide accumulation during the early phase of hindlimb suspension (7 days) but had little effect on muscle size and insulin sensitivity.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00330.2019
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
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  • 2
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    Reversal of deficits in aged skeletal muscle during disuse and recovery in response to treatment with a secrotome product derived from partially differentiated human pluripotent stem cells
    Springer Science and Business Media LLC ; 2021
    In:  GeroScience Vol. 43, No. 6 ( 2021-12), p. 2635-2652
    Details
    In: GeroScience, Springer Science and Business Media LLC, Vol. 43, No. 6 ( 2021-12), p. 2635-2652
    Abstract: Aged individuals are at risk to experience slow and incomplete muscle recovery following periods of disuse atrophy. While several therapies have been employed to mitigate muscle mass loss during disuse and improve recovery, few have proven effective at both. Therefore, the purpose of this study was to examine the effectiveness of a uniquely developed secretome product (STEM) on aged skeletal muscle mass and function during disuse and recovery. Aged (22 months) male C57BL/6 were divided into PBS or STEM treatment ( n  = 30). Mice within each treatment were assigned to either ambulatory control (CON; 14 days of normal cage ambulation), 14 days of hindlimb unloading (HU), or 14 days of hindlimb unloading followed by 7 days of recovery (recovery). Mice were given an intramuscular delivery into the hindlimb muscle of either PBS or STEM every other day for the duration of their respective treatment group. We found that STEM-treated mice compared to PBS had greater soleus muscle mass, fiber cross-sectional area (CSA), and grip strength during CON and recovery experimental conditions and less muscle atrophy and weakness during HU. Muscle CD68 +, CD11b + and CD163 + macrophages were more abundant in STEM-treated CON mice compared to PBS, while only CD68 + and CD11b + macrophages were more abundant during HU and recovery conditions with STEM treatment. Moreover, STEM-treated mice had lower collagen IV and higher Pax7 + cell content compared to PBS across all experimental conditions. As a follow-up to examine the cell autonomous role of STEM on muscle, C2C12 myotubes were given STEM or horse serum media to examine myotube fusion/size and effects on muscle transcriptional networks. STEM-treated C2C12 myotubes were larger and had a higher fusion index and were related to elevated expression of transcripts associated with extracellular matrix remodeling. Our results demonstrate that STEM is a unique cocktail that possesses potent immunomodulatory and cytoskeletal remodeling properties that may have translational potential to improve skeletal muscle across a variety of conditions that adversely effect aging muscle.
    Type of Medium: Online Resource
    ISSN: 2509-2715 , 2509-2723
    URL: Article
    DOI: 10.1007/s11357-021-00423-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2886418-9
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  • 3
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    Acute Effects of Cheddar Cheese Consumption on Circulating Amino Acids and Human Skeletal Muscle
    MDPI AG ; 2021
    In:  Nutrients Vol. 13, No. 2 ( 2021-02-13), p. 614-
    Details
    In: Nutrients, MDPI AG, Vol. 13, No. 2 ( 2021-02-13), p. 614-
    Abstract: Cheddar cheese is a protein-dense whole food and high in leucine content. However, no information is known about the acute blood amino acid kinetics and protein anabolic effects in skeletal muscle in healthy adults. Therefore, we conducted a crossover study in which men and women (n = 24; ~27 years, ~23 kg/m2) consumed cheese (20 g protein) or an isonitrogenous amount of milk. Blood and skeletal muscle biopsies were taken before and during the post absorptive period following ingestion. We evaluated circulating essential and non-essential amino acids, insulin, and free fatty acids and examined skeletal muscle anabolism by mTORC1 cellular localization, intracellular signaling, and ribosomal profiling. We found that cheese ingestion had a slower yet more sustained branched-chain amino acid circulation appearance over the postprandial period peaking at ~120 min. Cheese also modestly stimulated mTORC1 signaling and increased membrane localization. Using ribosomal profiling we found that, though both milk and cheese stimulated a muscle anabolic program associated with mTORC1 signaling that was more evident with milk, mTORC1 signaling persisted with cheese while also inducing a lower insulinogenic response. We conclude that Cheddar cheese induced a sustained blood amino acid and moderate muscle mTORC1 response yet had a lower glycemic profile compared to milk.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu13020614
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2518386-2
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  • 4
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    Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk
    Elsevier BV ; 2023
    In:  Gastroenterology Vol. 165, No. 5 ( 2023-11), p. 1136-1150
    Details
    In: Gastroenterology, Elsevier BV, Vol. 165, No. 5 ( 2023-11), p. 1136-1150
    Type of Medium: Online Resource
    ISSN: 0016-5085
    URL: Article
    DOI: 10.1053/j.gastro.2023.07.017
    RVK:
    XA 44500
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 5
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    Disuse‐induced muscle fibrosis, cellular senescence, and senescence‐associated secretory phenotype in older adults are alleviated during re‐ambulation with metformin pre‐treatment
    Wiley ; 2023
    In:  Aging Cell
    Details
    In: Aging Cell, Wiley
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1474-9718 , 1474-9726
    URL: Article
    DOI: 10.1111/acel.13936
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 6
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    The impact of skeletal muscle contraction on CD146 + Lin − pericytes
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Cell Physiology Vol. 317, No. 5 ( 2019-11-01), p. C1011-C1024
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 317, No. 5 ( 2019-11-01), p. C1011-C1024
    Abstract: Unaccustomed resistance exercise can initiate skeletal muscle remodeling and adaptive mechanisms that can confer protection from damage and enhanced strength with subsequent stimulation. The myofiber may provide the primary origin for adaptation, yet multiple mononuclear cell types within the surrounding connective tissue may also contribute. The purpose of this study was to evaluate the acute response of muscle-resident interstitial cells to contraction initiated by electrical stimulation (e-stim) and subsequently determine the contribution of pericytes to remodeling as a result of training. Mice were subjected to bilateral e-stim or sham treatment. Following a single session of e-stim, NG2 + CD45 − CD31 − (NG2 + Lin − ) pericyte, CD146 + Lin − pericyte, and PDGFRα + fibroadipogenic progenitor cell quantity and function were evaluated via multiplex flow cytometry and targeted quantitative PCR. Relative quantity was not significantly altered 24 h postcontraction, yet unique gene signatures were observed for each cell population at 3 h postcontraction. CD146 + Lin − pericytes appeared to be most responsive to contraction, and upregulation of genes related to immunomodulation and extracellular matrix remodeling was observed via RNA sequencing. Intramuscular injection of CD146 + Lin − pericytes did not significantly increase myofiber size yet enhanced ECM remodeling and angiogenesis in response to repeated bouts of e-stim for 4 wk. The results from this study provide the first evidence that CD146 + Lin − pericytes are responsive to skeletal muscle contraction and may contribute to the beneficial outcomes associated with exercise.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00156.2019
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477334-X
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  • 7
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    Cognitive function is preserved in aged mice following long-term β-hydroxy β-methylbutyrate supplementation
    Informa UK Limited ; 2020
    In:  Nutritional Neuroscience Vol. 23, No. 3 ( 2020-03-03), p. 170-182
    Details
    In: Nutritional Neuroscience, Informa UK Limited, Vol. 23, No. 3 ( 2020-03-03), p. 170-182
    Type of Medium: Online Resource
    ISSN: 1028-415X , 1476-8305
    URL: Article
    DOI: 10.1080/1028415X.2018.1483101
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2020
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  • 8
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    An accumulation of muscle macrophages is accompanied by altered insulin sensitivity after reduced activity and recovery
    Wiley ; 2019
    In:  Acta Physiologica Vol. 226, No. 2 ( 2019-06)
    Details
    In: Acta Physiologica, Wiley, Vol. 226, No. 2 ( 2019-06)
    Abstract: Mechanisms underlying physical inactivity‐induced insulin resistance are not well understood. In addition to a role in muscle repair, immune cell populations such as macrophages may regulate insulin sensitivity. Aim The aim of this study was to examine if the dynamic changes in insulin sensitivity during and after recovery from reduced physical activity corresponded to changes in skeletal muscle macrophages. Methods In this prospective clinical study, we collected muscle biopsies from healthy older adults (70 ± 2 years, n = 12) before and during a hyperinsulinaemic‐euglycaemic clamp and this occurred before (PRE) and after 2‐week reduced physical activity (RA), and following 2‐week of recovery (REC). Insulin sensitivity (hyperinsulinaemic‐euglycaemic clamp), skeletal muscle mRNA expression of inflammatory markers, and immunofluorescent quantification of skeletal muscle macrophages, myofibre‐specific satellite cell and capillary content were assessed. Results Insulin sensitivity was decreased following reduced activity and rebounded following recovery above PRE levels. We observed an increase ( P   〈  0.01) in muscle macrophages (CD68 + CD206 + : 190 [55, 324]; CD11b + CD206 + : 117 [28, 205]% change from PRE) and CD68 (2.4 [1.4, 3.4] ‐fold) and CCL2 (1.9 [1.3, 2.5]‐fold) mRNA following RA concurrent with increased ( P   〈  0.03) satellite cells (55 [6, 104]%) in slow‐twitch myofibres. Moreover, the distance of satellite cells to the nearest capillary was increased 7.7 (1.7, 13.7) µm in fast‐twitch myofibres at RA ( P  = 0.007). Changes in macrophages were positively associated with increased insulin sensitivity following RA ( R   〉  0.57, P   〈  0.05). Conclusion These findings suggested that a dynamic response of skeletal muscle macrophages following acute changes in physical activity in healthy older adults is related to insulin sensitivity.
    Type of Medium: Online Resource
    ISSN: 1748-1708 , 1748-1716
    URL: Issue
    URL: Article
    DOI: 10.1111/apha.2019.226.issue-2
    DOI: 10.1111/apha.13251
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2617148-X
    detail.hit.zdb_id: 2219379-0
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  • 9
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    Macrophage immunomodulation accelerates skeletal muscle functional recovery in aged mice following disuse atrophy
    American Physiological Society ; 2022
    In:  Journal of Applied Physiology Vol. 133, No. 4 ( 2022-10-01), p. 919-931
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 133, No. 4 ( 2022-10-01), p. 919-931
    Abstract: Poor recovery of muscle size and strength with aging coincides with a dysregulated macrophage response during the early stages of regrowth. Immunomodulation in the form of ex vivo cytokine (macrophage-colony stimulating factor) or polarized macrophage delivery has been demonstrated to improve skeletal muscle regeneration. However, it is unclear if these macrophage-promoting approaches would be effective to improve skeletal muscle recovery following disuse in aged animals. Here, we isolated bone marrow-derived macrophages from donor mice of different ages under various experimental conditions and polarized them into proinflammatory macrophages. Macrophages were delivered intramuscularly into young adult or aged recipient mice during the early recovery period following a period of hindlimb unloading (HU). Delivery of proinflammatory macrophages from donor young adults or aged mice was sufficient to increase muscle function of aged mice during the recovery period. Moreover, proinflammatory macrophages derived from aged donor mice collected during recovery were similarly able to increase muscle function of aged mice following disuse. In addition to the delivery of macrophages, we showed that the intramuscular injection of the cytokine, macrophage-colony stimulating factor, to the muscle of aged mice following HU was able to increase muscle macrophage content and muscle force production during recovery. Together, these results suggest that macrophage immunomodulation approaches in the form of ex vivo proinflammatory macrophage or macrophage-colony stimulating factor delivery during the early recovery phase following disuse atrophy were sufficient to restore the loss of aged skeletal muscle function. NEW & NOTEWORTHY A single intramuscular administration of polarized macrophages into muscles of aged mice following a bout of disuse atrophy was sufficient to improve functional recover similarly to young adults after disuse atrophy regardless of the age or experimental condition of the donor mice. Additionally, intramuscular delivery of macrophage-colony stimulating factor into aged mice was similarly effective. Targeting macrophage function early during the regrowth phase may be a novel tool to bolster muscle recovery in aging.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.00374.2022
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1404365-8
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    SSG: 31
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  • 10
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    Muscle disuse as hindlimb unloading in early postnatal mice negatively impacts grip strength in adult mice: a pilot study
    American Physiological Society ; 2023
    In:  Journal of Applied Physiology Vol. 134, No. 4 ( 2023-04-01), p. 787-798
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 134, No. 4 ( 2023-04-01), p. 787-798
    Abstract: Physical inactivity has many detrimental effects on health, yet the impact of physical inactivity in early life on muscle health in adulthood remains unknown. Early postnatal malnutrition has prolonged effects into adulthood and we propose that early postnatal (P) physical inactivity would have similar negative effects. To test this hypothesis, we exposed postnatal mice (∼ P28, C57BL/6J) to 14 days of physical inactivity (shortly after weaning, from ∼P28 to P42 days of age) in the form of muscle disuse with hindlimb unloading (HU). After this early-life physical inactivity, they were allowed to normally ambulate until 5 mo of age ( P140, adulthood) when they underwent 14 days of HU with and without 7-day recovery. They were then tested for physical function (grip strength) and muscles were extracted and weighed. Immunofluorescence was carried out on these muscle cross sections for analysis of myofiber cross-sectional area (fCSA), macrophage density (CD68 + cells), and extracellular matrix (ECM) area. Muscle weights and fCSA and myofiber diameter were used to quantify changes in muscle and fiber size. Compared with age-matched controls, no notable effects of early-life physical inactivity (HU) on skeletal muscle and myofiber size were observed. However, a significant reduction in adult grip strength was observed in those exposed to HU early in life. This was associated with reduced muscle macrophages and increased ECM area. Exposure to a short period of early life disuse has negative enduring effects into adulthood impacting grip strength, muscle macrophages, and muscle composition as low muscle quality. NEW & NOTEWORTHY We demonstrate that early life disuse resulted in less grip strength in adulthood. Analysis of muscle composition demonstrated no loss of whole muscle or myofiber size indicating lower muscle quality akin to premature aging. This poor muscle quality was characterized by altered muscle macrophages and extracellular matrix area. We demonstrate intriguing correlations between this loss of grip strength and muscle macrophages and also area of noncontractile tissue in the muscle.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.00681.2022
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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