Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.

Multi-omic rejuvenation and life span extension on exposure to youthful circulation.

Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on biological age and long-term health is unknown. Here we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a global multi-omic rejuvenation effect. In addition, old HPB mice showed gene expression changes opposite to aging but akin to several life span-extending interventions. Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span.

Meteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling.

Pathologies associated with sarcopenia include decline in muscular strength, lean mass and regenerative capacity. Despite the substantial impact on quality of life, no pharmacological therapeutics are available to counteract the age-associated decline in functional capacity and/or, resilience. Evidence suggests immune-secreted cytokines can improve muscle regeneration, a strategy which we leverage in this study by rescuing the age-related deficiency in Meteorin-like through several in vivo add-back models. Notably, the intramuscular, peptide injection of recombinant METRNL was sufficient to improve muscle regeneration in aging. Using ex vivo media exchange and in vivo TNF inhibition, we demonstrate a mechanism of METRNL action during regeneration, showing it counteracts a pro-fibrotic gene program by triggering TNFα-induced apoptosis of fibro/adipogenic progenitor cells. These findings demonstrate therapeutic applications for METRNL to improve aged muscle, and show Fibro/Adipogenic Progenitors are viable therapeutic targets to counteract age-related loss in muscle resilience.

A novel movement system screen for primary care providers: a multisite, observational study.

CONTEXT: Movement of the human body is essential for the interaction of an individual within their environment and contributes to both physical and emotional quality of life. Movement system disorders (MSDs) are kinesiopathologic conditions that result from either altered movement patterns, trauma, or pathology. A screening tool may facilitate earlier diagnosis and treatment of acute MSDs. This tool could prevent progression to chronic conditions, leading to better patient outcomes and quality of life. OBJECTIVES: Our study evaluated whether a screening tool would be able to accurately screen individuals for MSDs, explore comorbidities that may predict the prevalence of MSDs, and identify why people do not discuss these problems with their primary care provider (PCP). METHODS: A multisite, observational study in a primary care setting. Data were analyzed to determine the psychometric properties of the screening question. Logistic regression was performed to explore the relationship of comorbidities with MSDs. Thematic analysis was performed to explore why patients do not discuss these issues with their PCP. RESULTS: The point prevalence of MSDs was determined to be 78%. The sensitivity of the screening question was determined to be good (70%). Arthritis, obesity, sleep disorders, and gastroesophageal reflux disease (GERD) were significant predictors for an MSD. Thematic analysis regarding why patients do not discuss the MSD with their physician revealed: (1) the perceived lack of importance of the problem; (2) the lack of access to healthcare, and (3) the acuity of the problem. CONCLUSIONS: Screening for an MSD and associated comorbidities could prevent the transition of acute conditions to chronic conditions. If PCPs can identify predictors and factors associated with an MSD, they may be able to screen for MSDs more effectively. Earlier identification of MSDs may facilitate earlier treatment and prevent costs associated with resulting chronic disorders and persistent pain and disability.

Decreased Sleep and Subjective Well-Being as Independent Predictors of Injury in Female Collegiate Volleyball Players.

BACKGROUND: The relationship among sleep duration, subjective well-being, and injury risk in athletes is poorly defined. PURPOSE: To evaluate the independent effects of sleep duration, sleep quality, and subjective well-being on in-season injuries in collegiate female volleyball athletes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: During a 9-month competitive season, 17 female National Collegiate Athletic Association (NCAA) Division I volleyball players reported mood, fatigue, stress, soreness, sleep duration (hours), and sleep quality every morning. Well-being measures were recorded from 0 (worst) to 5 (best), and all time-loss injuries were recorded by the team athletic trainer. Separate mixed-effects logistic regression models were used to evaluate the effects of sleep and subjective well-being on in-season injury. Each well-being variable was also included in a separate mixed-effects logistic regression model with sleep duration as a covariate. RESULTS: A total of 54 injuries were recorded during the study period. Compared with days without an injury, mood, fatigue, stress, soreness, sleep quality, and sleep duration were significantly worse the day before an injury occurred. In the separate prediction models, in-season injury was significantly predicted by fatigue (odds ratio [OR], 0.56 [95% CI, 0.36-0.86]; P = .008), mood (OR, 0.52 [95% CI, 0.35-0.78]; P = .002), stress (OR, 0.63 [95% CI, 0.42-0.94]; P = .023), soreness (OR, 0.54 [95% CI, 0.38-0.79]; P = .001), sleep quality (OR, 0.49 [95% CI, 0.34-0.7]; P < .001), and sleep duration (OR, 0.69 [95% CI, 0.55-0.87]; P = .001). In the multivariable models, sleep duration remained a significant independent predictor in each of the subsequent multivariable models (OR, 0.72-0.74; P < .05 for all), as did mood (OR, 0.55 [95% CI, 0.36-0.83); P = .005) and soreness (OR, 0.57 [95% CI, 0.39-0.83]; P = .003), while fatigue (OR, 0.65 [95% CI, 0.42-1]; P = .054) and stress (OR, 0.68 [95% CI, 0.45-1]; P = .061) no longer reached statistical significance. CONCLUSION: Increased sleep duration, mood, and decreased soreness were independently associated with a reduced risk of in-season injury in this cohort of female NCAA volleyball players.

The AMPK/p27Kip1 Pathway as a Novel Target to Promote Autophagy and Resilience in Aged Cells.

Once believed to solely function as a cyclin-dependent kinase inhibitor, p27Kip1 is now emerging as a critical mediator of autophagy, cytoskeletal dynamics, cell migration and apoptosis. During periods of metabolic stress, the subcellular location of p27Kip1 largely dictates its function. Cytoplasmic p27Kip1 has been found to be promote cellular resilience through autophagy and anti-apoptotic mechanisms. Nuclear p27Kip1, however, inhibits cell cycle progression and makes the cell susceptible to quiescence, apoptosis, and/or senescence. Cellular location of p27Kip1 is regulated, in part, by phosphorylation by various kinases, including Akt and AMPK. Aging promotes nuclear localization of p27Kip1 and a predisposition to senescence or apoptosis. Here, we will review the role of p27Kip1 in healthy and aging cells with a particular emphasis on the interplay between autophagy and apoptosis.

Decreased ventricular size and mass mediate the reduced exercise capacity in adolescents and adults born premature.

BACKGROUND: Premature birth is associated with lower levels of cardiorespiratory fitness (CRF) but the underlying mechanisms responsible remain unclear. This study assessed whether differences in cardiac morphology or function mediate differences in CRF among adolescents and young adults born preterm. METHODS: Adolescents and young adults born moderately to extremely premature (gestational age ≤ 32 weeks or birth weight < 1500 g) and age-matched term born participants underwent resting cardiac MRI and maximal exercise testing. Mediation analysis assessed whether individual cardiovascular variables accounted for a significant proportion of the difference in maximal aerobic capacity between groups. RESULTS: Individuals born preterm had lower VO2max than those born term (41.7 ±â€¯8.6 v 47.5 ±â€¯8.7, p < 0.01). Several variables differed between term and preterm born subjects, including systolic and diastolic blood pressure, mean pulmonary artery pressure, indexed left ventricular end-diastolic volume (LVEDVi), right ventricular end-diastolic volume (RVEDVi), LV mass (LVMi), LV stroke volume index (LVSVi), and LV strain (p < 0.05 for all). Of these variables, LVEDVi, RVEDVi, LVSVi, LVMi, and LV longitudinal strain were significantly related to VO2max (p < 0.05 for all). Significant portions of the difference in VO2max between term and preterm born subjects were mediated by LVEDVi (74.3%, p = 0.010), RVEDVi (50.6%, p = 0.016), and LVMi (43.0%, p = 0.036). CONCLUSIONS: Lower levels of CRF in adolescents and young adults born preterm are mediated by differences in LVEDVi, RVEDVi, and LVMi. This may represent greater risk for long-term cardiac morbidity and mortality in preterm born individuals.