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Extended periods of bed rest and limb immobilization are required for healing post‐injury or disease, yet disuse can result in significant muscle atrophy and decreased quality of life in older adults. Physical rehabilitation is commonly prescribed to recover these deficits, yet accumulation of reactive oxygen species and sustained rates of protein degradation persist during the rehabilitation period that can significantly delay or prevent recovery. Pericytes, considered the primary mesenchymal and vascular stromal cell in skeletal muscle, secrete beneficial factors that maintain baseline muscle mass, yet minimal information exists regarding the pericyte response to disuse and recovery. In the current study, single‐cell RNA sequencing and functional assays were performed to demonstrate that pericytes in mouse skeletal muscle lose the capacity to synthesize antioxidants during disuse and recovery. This information was used to guide the design of a strategy in which healthy donor pericytes were stimulated with hydrogen peroxide (H2O2) to produce small extracellular vesicles (sEVs) that effectively restored myofibre size in adult and aged muscle after disuse. Proteomic assessment detected 11 differentially regulated proteins in primed sEVs that may account for recovery of muscle, including proteins associated with extracellular matrix composition and anti‐inflammatory and antioxidant processes. This study demonstrates that healthy H2O2‐primed pericyte‐derived sEVs effectively improve skeletal muscle recovery after immobilization, presenting a novel acellular approach to rebuild muscle mass in older adults after a period of disuse. Key points: Previous studies suggest that prolonged oxidative stress is a barrier to skeletal muscle recovery after a period of immobilization.In this study we demonstrate that muscle‐resident perivascular stromal cells (pericytes) become dysfunctional and lack the capacity to mount an antioxidant defence after disuse in mice.Hydrogen peroxide treatment of healthy pericytes in vitro simulates the release of small extracellular vesicles (sEVs) that effectively recover skeletal muscle fibre size and extracellular matrix remodelling in young adult and aged mice after disuse.Pericyte‐derived sEVs present a novel acellular strategy to recover skeletal muscle after disuse. [ABSTRACT FROM AUTHOR]

The goal of this study was to evaluate if combinations of ingredients with known anti-cachexia benefits (Fish oil-FO with either curcumin or Green tea extract-GTE), have adverse effects on tumor growth, using human carcinoma xenograft mice models. FO (EPA/DHA 360 mg/kg bw), GTE (90 mg/kg bw), and curcumin (180 mg/kg bw) were administered orally, alone or in combination, to nude mice bearing either A549 human non-small cell lung carcinoma or SW620 human colon carcinoma tumors. Bodyweight, tumor growth, survival time, and other clinical endpoints were assessed. The ingredients either alone or in combinations were well tolerated in both lung and colon tumor-bearing mice. There were no significant group differences between individual or combination treatments for tumor growth (A549 or SW620) as measured by the median time in days to endpoint of tumor volume (TTE). TTE results indicate that these ingredients (alone or combinations) did not adversely impact tumor growth. No significant differences in body weights or survival were observed between controls and treatment groups indicating no adverse health effects of the ingredients. In conclusion, FO, GTE or curcumin administered as monotherapies and in combination were well tolerated and displayed no adverse effects on tumor growth in mouse xenograft models of lung and colon cancer. [ABSTRACT FROM AUTHOR]

Radiation-induced oral mucositis (RIOM) is a painful, dose-limiting toxicity in cancer therapy. RIOM was induced by radiation on the left buccal pouch mucosa of Golden Syrian hamsters (n = 8/group). Animals were treated topically with polyphenols (Curcumin or Quercetin) or amino acids/metabolite mixtures (Alanyl-Glutamine or Arginine + Glutamine + β-Hydroxy β-methylbutyric acid (Arg/Gln/HMB)) for over 20 day. Progression of RIOM was assessed using a standard visual scoring six-point scale, for differences in severity of mucositis (score ≥3) (Chi-square analysis) and in the daily group scores (Mann-Whitney rank sum test). Compared to the controls, there was a significant reduction in number of days with severe RIOM (score ≥3) in the treatment groups: Curcumin (50 μg/ml) = 17%; Control = 38.5%, p < 0.001; Quercetin (50 μg/ml) = 27.6% and Quercetin (100 μg/ml) = 25%; Control = 41.3%, p = 0.007 and p = 0.001, respectively; Arg/Gln/HMB (50 mg/ml) = 31.9%; Control = 50.0%, p = 0.040. In addition, Curcumin (50 μg/ml), Quercetin (100 μg/ml) and Arg/Gln/HMB (100 mg/ml) groups had lower mucositis scores (≥3) on at least two consecutive time points over the course of the study than their respective controls. There were no significant group differences in deaths or body weight. This study demonstrates the potential benefits of topical application of either plant polyphenols or amino acid/metabolite mixtures in addressing severity and progression of RIOM. [ABSTRACT FROM AUTHOR]

Extended bed rest or limb immobilization can significantly reduce skeletal muscle mass and function. Recovery may be incomplete, particularly in older adults. Our laboratory recently reported that vascular mural cell (pericyte) quantity is compromised after immobilization and appropriate replacement immediately before remobilization can effectively recover myofiber size in mice. Identification of a single cell surface marker for isolation of the most therapeutic pericyte would streamline efforts to optimize muscle recovery. The purpose of this study was to compare the capacity for neural/glial antigen 2 (Cspg4/NG2þ) and melanoma cell adhesion molecule (Mcam/CD146þ) positive pericytes to uniquely recover skeletal muscle post-disuse. A single hindlimb from adult C57BL/6J mice was immobilized in full dorsiflexion via a surgical staple inserted through the center of the foot and body of the gastrocnemius. Fourteen days after immobilization, the staple was removed and pericytes, either NG2þCD45-CD31-[Lin-], CD146þNG2-Lin-, or CD146þLin-pericytes, were injected into the atrophied tibialis anterior (TA) muscle. TA muscles were excised 14 days after transplantation and remobilization. Pericyte transplantation did not significantly improve muscle mass or myofiber cross-sectional area (CSA) after 14 days of remobilization. However, injection of CD146þ pericytes significantly increased Type IIa quantity, capillarization, and collagen remodeling compared with NG2þ pericytes (P < 0.05). Our results suggest that selection of pericytes based on CD146 rather than NG2 results in the isolation of therapeutic mural cells with high capacity to positively remodel skeletal muscle after a period of immobilization. NEW & NOTEWORTHY In this study, pericytes were isolated from mouse skeletal muscle based on cell surface marker expression of neural/glial antigen 2 (NG2) or melanoma cell adhesion molecule (Mcam/CD146) and then compared for the capacity to recover skeletal muscle after a period of immobilization in recipient mice. We report that CD146þLin-pericytes exhibit higher capacity than NG2þLin-pericytes to recover Type IIa fiber quantity, capillary content, and collagen turnover after disuse. [ABSTRACT FROM AUTHOR]

Anabolic resistance to a mechanical stimulus may contribute to the loss of skeletal muscle mass observed with age. In this study, young and aged mice were injected with saline or human LM-111 (1 mg/kg). One week later, the myotendinous junction of the gastrocnemius muscle was removed via myotenectomy (MTE), thus placing a chronic mechanical stimulus on the remaining plantaris muscle for 2 weeks. LM-111 increased α7B integrin protein expression and clustering of the α7B integrin near DAPI+ nuclei in aged muscle in response to MTE. LM-111 reduced CD11b+ immune cells, enhanced repair, and improved the growth response to loading in aged plantaris muscle. These results suggest that LM-111 may represent a novel therapeutic approach to prevent and/or treat sarcopenia. [ABSTRACT FROM AUTHOR]

β-hydroxy β-methylbutyrate (HMB) is a nutritional supplement purported to enhance skeletal muscle mass and strength, as well as cognitive function in older adults. The purpose of this study was to determine the potential for long-term HMB supplementation to preserve muscle function and cognition in aged mice, as well as provide evidence of a link between vessel-associated pericyte function and outcomes. Four- (Adult/Ad) and 17 month-old (Aged/Ag) C57BL/6J mice consumed chow containing 600 mg/kg BW/day of either Ca-HMB (Ad, n=16; Ag, n=17) or Ca-Lactate (Ad, n=16; Ag, n=17) for 6 months. HMB did not prevent age-related reductions in muscle mass, strength and coordination (Age main effect, P<0.05). The rate of muscle protein synthesis decreased within the mitochondrial fraction (age main effect, P<0.05), and this decline was not prevented with HMB. Despite no change in muscle mass or function, an age-dependent reduction in active avoidance learning was attenuated with HMB (Age and HMB main effects, P<0.05). Age detrimentally impacted muscle-resident pericyte gene expression with no recovery observed with HMB, whereas no changes in brain-resident pericyte quantity or function were observed with age or HMB. The findings from this study suggest that prolonged HMB supplementation starting in adulthood may preserve cognition with age. [ABSTRACT FROM AUTHOR]

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 post contraction, yet unique gene signatures were observed for each cell population at 3 h post contraction. 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. [ABSTRACT FROM AUTHOR]