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The aim of this study was to investigate whether baseline values and acute and chronic changes in androgen receptors (AR) markers, including total AR, cytoplasmic (cAR), and nuclear (nAR) fractions, as well as DNA-binding activity (AR-DNA), are involved in muscle hypertrophy responsiveness by comparing young nonresponder and responder individuals. After 10 wk of resistance training (RT), participants were identified as nonresponders using two typical errors (TE) obtained through two muscle cross-sectional area (mCSA) ultrasound measurements (2 × TE; 4.94%), and the highest responders within our sample were numerically matched. Muscle biopsies were performed at baseline, 24 h after the first RT session (acute responses), and 96 h after the last session (chronic responses). AR, cAR, and nAR were analyzed using Western blotting, and AR-DNA was analyzed using an ELISA-oligonucleotide assay. Twelve participants were identified as nonresponders (ΔmCSA: -1.32%) and 12 as responders (ΔmCSA: 21.35%). There were no baseline differences between groups in mCSA, AR, cAR, nAR, or AR-DNA (P > 0.05). For acute responses, there was a significant difference between nonresponders (+19.5%) and responders (-14.4%) in AR-DNA [effect size (ES) = -1.39; 95% confidence interval (CI): -2.53 to -0.16; P = 0.015]. There were no acute between-group differences in any other AR markers (P > 0.05). No significant differences between groups were observed in chronic responses across any AR markers (P > 0.05). Nonresponders and responders presented similar baseline, acute, and chronic results for the majority of the AR markers. Thus, our findings do not support the influence of AR markers on muscle hypertrophy responsiveness to RT in untrained individuals.NEW & NOTEWORTHY We explored, for the first time, the influence of androgen receptor (AR) through the separation of cytoplasmic and nuclear cell fractions [i.e., cytoplasmic androgen receptor (cAR), nuclear androgen receptor (nAR), and androgen receptor DNA-binding activity (AR-DNA)] on muscle hypertrophy responsiveness to resistance training. The absence of muscle hypertrophy in naïve individuals does not seem to be explained by baseline values, and acute or chronic changes in AR markers.

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The present study aimed to assess the effectiveness and functional adverse effects of a single and multiple injections of botulinum toxin A (BoNT-A) for masseter hypertrophy (MH). Twenty-six women complaining about lower third facial enlargement due to MH, received 75 U of BoNT-A (abobotulinum toxin) in each masseter muscles. After 3 months, patients were randomly assigned to receive a second treatment session of Saline Solution: (G1; n = 11) or BoNT-A: (G2; n = 12). Muscle thickness (ultrasound), electrical activity (electromyography; EMG), masticatory performance, and subjective perception of MH were evaluated. Follow-up was performed at 1, 3 and 6 months. Muscle thickness, EMG activity, and masticatory performance were analyzed using ANOVA two-way and Sidak test as post-hoc. Masticatory performance was analyzed by the Friedman's test and Mann-Whitney test. Regarding inter-groups comparisons, there was a significant decrease in the left masseter muscle thickness in the G2 group at the 6 month follow-up (p < 0.02). For EMG, significant differences were evident at the 6 month assessment, with higher masseter activity for G1 (p < 0.05). For masticatory performance, no significant differences were observed throughout the study (p > 0.05) and a higher improvement in subjective perception of MH was observed in the 1 month follow-up for G2 (p < 0.05). In conclusion, BoNT-A is effective for MH, however multiple injections cause functional adverse effects in masseter muscle.

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ABSTRACT: de Lemos Muller, CH, Farinha, JB, Leal-Menezes, R, and Ramis, TR. Aerobic training with blood flow restriction on muscle hypertrophy and strength: systematic review and meta-analysis. J Strength Cond Res 38(7): 1341-1349, 2024-Integrating strength and endurance training in a single exercise session, even on separate days, can be physically demanding and time-consuming. Therefore, there is a growing interest in identifying efficient training methods that can concurrently enhance cardiovascular and neuromuscular performance through a singular training modality. This study conducted a systematic review and meta-analysis to explore the effects of aerobic training with blood flow restriction (AT + BFR) on muscle hypertrophy and strength gains in healthy individuals. Our study was registered at PROSPERO and used multiple databases (PubMed, Embase, Scopus, and Web of Science), seeking clinical trials that examined AT + BFR influence on muscle hypertrophy and strength gains in individuals aged 18-60 years and comparing with aerobic training without BFR. The risk of bias and method quality were assessed using the ROB2.0 tool and PEDro scale, respectively, and the quality of evidence was evaluated with the GRADE method. A random-effects model was used for meta-analysis, and standardized mean difference (SMD) was calculated for each outcome. Of 4,462 records, 29 full texts were assessed for eligibility, with 7 articles meeting the inclusion criteria. The results indicated that AT + BFR was more beneficial for inducing muscle hypertrophy than aerobic training without BFR (SMD [95% CI] = 0.86 [0.37-1.35]; I2 = 42%). Furthermore, AT + BFR was associated with greater improvements in muscle strength (SMD [95% CI] = 0.41 [0.10-0.72]; I2 = 0%). Despite the generally high risk of bias for both outcomes, these encouraging findings underscore the clinical significance of AT + BFR as a compelling tool for enhancing neuromuscular parameters.

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BACKGROUND: This study aimed to elucidate the effects of botulinum toxin A (BoNT-A) treatment for patients diagnosed with masseter hypertrophy on the temporalis muscle, with a particular focus on assessing alterations in muscle thickness, electromyographic (EMG) activity, and the development of muscle pain. METHODS: The present randomized triple-blinded clinical trial enrolled 26 female participants aged between 25 and 50 years complaining about masseter hypertrophy. Participants received 75U of BoNT-A (abobotulinumtoxinA) in both masseter muscles and after three months were randomized to receive a second treatment session of saline solution (S-BoNT-A) or BoNT-A (M-BoNT-A). Longitudinal assessments included temporalis muscle thickness through ultrasound, EMG activity, subjective pain, and masseter prominence severity after one, three, and six months of the first injection session. Muscle thickness, EMG, and subjective pain were analysed using two-way ANOVA with repeated measures and post hoc Sidak test, and for masseter prominence severity, Friedman and Mann-Whitney tests were used. RESULTS: Regarding inter-group comparisons, a higher muscle thickness (p < 0.02) and a higher EMG activity (p < 0.01) were found in the M-BoNT-A group at the 6-month follow-up. For subjective pain assessments, inter-group comparisons showed a higher prevalence of painful regions in M-BoNT-A group at the 6-month follow-up (p < 0.02). No significant differences were found in masseter prominence severity at the 6 months assessment between groups. CONCLUSION: BoNT-A treatment for masseter hypertrophy lead to structural and functional changes in the temporalis muscle, presenting higher changes after multiple injections of this treatment. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

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ABSTRACT: Nunes, JP, Blazevich, AJ, Schoenfeld, BJ, Kassiano, W, Costa, BDV, Ribeiro, AS, Nakamura, M, Nosaka, K, and Cyrino, ES. Determining changes in muscle size and architecture after exercise training: One site does not fit all. J Strength Cond Res 38(4): 787-790, 2024-Different methods can be used to assess muscle hypertrophy, but the effects of training on regional changes in muscle size can be detected only using direct muscle measurements such as muscle thickness, cross-sectional area, or volume. Importantly, muscle size increases vary across regions within and between muscles after resistance training programs (i.e., heterogeneous, or nonuniform, muscle hypertrophy). Muscle architectural changes, including fascicle length and pennation angle, after resistance and stretch training programs are also region-specific. In this paper, we show that the literature indicates that a single-site measure of muscle shape does not properly capture the effects achieved after exercise training interventions and that conclusions concerning the magnitude of muscle adaptations can vary substantially depending on the muscle site to be examined. Thus, we propose that measurements of muscle size and architecture should be completed at multiple sites across regions between the agonist muscles within a muscle group and along the length of the muscles to provide an adequate picture of training effects.

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Combined allergic rhinitis and asthma syndrome (CARAS) is an airway-type 2 immune response with a profuse inflammatory process widely affecting the world population. Due to the compromise of quality of life and the lack of specific pharmacotherapy, the search for new molecules becomes relevant. This study aimed to evaluate the effectiveness of the Morita-Bailys-Hillman adduct (CISACN) treatment in the CARAS experimental model. Female BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with CISACN. The treatment decreased the eosinophil migration to the nasal and lung cavities and tissues and the goblet cell hyperplasia/hypertrophy, attenuated airway hyperactivity by reducing the hyperplasia/hypertrophy of the smooth muscle and the extracellular matrix's thickness. Also, the treatment reduced the clinical signs of rhinitis as nasal rubbing and sneezing in a histamine-induced nasal hyperreactivity assay. The immunomodulatory effect of CISACN was by reducing OVA-specific IgE serum level, and IL-33, IL-4, IL-13, and TGF-ß production, dependent on IFN-γ increase. Furthermore, the effect of CISACN on lung granulocytes was by decreasing the p-p38MAPK/p65NF-κB signaling pathway. Indeed, CISACN reduced the p38MAPK and p65NF-κB activation. These data demonstrated the anti-inflammatory and immunomodulatory effects of the CISACN with scientific support to become a pharmacological tool to treat airway inflammatory diseases.

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La presentación bilateral del absceso periamigdalino es poco frecuente. Su abordaje es controversial y se discute si realizar amigdalectomía en caliente versus diferida. Se presenta el caso de un paciente de sexo masculino, de 14 años, con odinofagia, trismo y fiebre. Presentaba hipertrofia amigdalina bilateral, pilares abombados y edema de paladar blando. Tomografía computada: hipertrofia amigdalina bilateral, con realce poscontraste, ambas con colección, edema con moderada estenosis faríngea. Se decidió internación para tratamiento endovenoso y amigdalectomía con drenaje bilateral. Resolución completa del cuadro con alta a las 48 horas. Ante la presencia de un absceso periamigdalino, debe considerarse la posibilidad de un absceso contralateral oculto. Debe ser diagnosticado y tratado adecuadamente para prevenir complicaciones. La amigdalectomía en caliente podría ser un tratamiento seguro y debería ser considerado en pacientes que serán sometidos a anestesia para drenaje. La decisión final debe ser determinada para cada caso en particular.

The bilateral presentation of peritonsillar abscess is uncommon. Its management is controversial and it has been argued whether a quinsy tonsillectomy or an interval tonsillectomy should be performed. Here we describe the case of a 14-year-old boy with sore throat, trismus, and fever. He had bilateral tonsillar hypertrophy, convex arches, and soft palate edema. Computed tomography: bilateral tonsillar hypertrophy, with post-contrast enhancement, both with collection, edema with moderate pharyngeal stenosis. The patient was hospitalized for intravenous therapy and tonsillectomy with bilateral drainage resulting in a complete resolution of his condition and discharge at 48 hours. In the presence of a peritonsillar abscess, an unsuspected contralateral abscess should be considered. It should be diagnosed and managed adequately to prevent complications. Quinsy tonsillectomy could be safe and should be considered in patients who will undergo anesthesia for abscess drainage. The final decision should be made for each patient on an individual basis.

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The magnitude of muscle hypertrophy in response to resistance training (RT) is highly variable between individuals (response heterogeneity). Manipulations in RT variables may modulate RT-related response heterogeneity; yet, this remains to be determined. Using a within-subject unilateral design, we aimed to investigate the effects of RT volume manipulation on whole muscle hypertrophy [quadriceps muscle cross-sectional area (qCSA)] among nonresponders and responders to a low RT dose (single-set). We also investigated the effects of RT volume manipulation on muscle strength in these responsiveness groups. Eighty-five older individuals [41M/44F, age = 68 ± 4 yr; body mass index (BMI) = 26.4 ± 3.7 kg/m2] had one leg randomly allocated to a single (1)-set and the contralateral leg allocated to four sets of unilateral knee-extension RT at 8-15 repetition maximum (RM) for 10-wk 2 days/wk. Pre- and postintervention, participants underwent magnetic resonance imaging (MRI) and unilateral knee-extension 1-RM strength testing. MRI typical error (2× TE = 3.27%) was used to classify individuals according to responsiveness patterns. n = 51 were classified as nonresponders (≤2× TE) and n = 34 as responders (>2× TE) based on pre- to postintervention change qCSA following the single-set RT protocol. Nonresponders to single-set training showed a dose response, with significant time × set interactions for qCSA and 1-RM strength, indicating greater gains in response to the higher volume prescription (time × set: P < 0.05 for both outcomes). Responders improved qCSA (time: P < 0.001), with a tendency toward higher benefit from the four sets RT protocol (time × set: P = 0.08); on the other hand, 1-RM increased similarly irrespectively of RT volume prescription (time × set: P > 0.05). Our findings support the use of higher RT volume to mitigate nonresponsiveness among older adults.NEW & NOTEWORTHY Using a within-subject unilateral design, we demonstrated that increasing resistance training (RT) volume may be a simple, effective strategy to improve muscle hypertrophy and strength gains among older adults who do not respond to low-volume RT. In addition, it could most likely be used to further improve hypertrophic outcomes in responders.

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The kidneys of male Squamata have an important reproductive function as some portions of the nephron may undergo hypertrophy, characterizing the sexual segment of the kidney (SSK). Although its function is still not completely understood, it is believed that the secretions produced by the SSK may act in the maintenance of spermatozoa. In this study, we investigated the reproductive biology of males of Notomabuya frenata based on the seasonal variation of the SSK. We performed macroscopic and microscopic evaluations of the male reproductive tract of museum specimens to characterize the SSK cycle. The nephron portion in which hypertrophy was observed was the collecting duct with secretory granules accumulation in the apical portion. SSK hypertrophy was observed in all seasons, with the tubule diameter in autumn differing from spring and the epithelium height showing no variation. Alcian Blue reacted positively to acid mucopolysaccharides in all seasons. Periodic acid-Schiff's reacted positively to neutral mucopolysaccharides in all seasons, except autumn. Both stains reacted only in the collecting duct. In addition, spermatozoa were found in the lumen of the SSK of one specimen examined. Cycle of the SSK varied seasonally as does the chemical composition of the secretions produced by the collecting duct. The reflux of spermatozoa into SSK may indicate that (1) these secretions act in sperm maintenance, and (2) possibly there is communication between the seminal and urinary ducts.

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PURPOSE: This study investigated the effect of progressively adding sets for the lower limb every 2 wk versus performing a constant set volume in resistance-trained males. METHODS: Thirty-one resistance-trained males (age = 24.4 ± 2.9 yr, height = 175.5 ± 6.5 cm, body mass = 80.1 ± 9.4 kg, body fat = 14.4% ± 3.1%, resistance training [RT] experience = 5.1 ± 2.2 yr; one-repetition maximum [1RM] barbell back squat: body mass ratio = 1.7 ± 0.1 a.u.) were randomly allocated into a constant group (CG, n = 10), a four-set progression group (4SG, n = 10) or a six-set progression group (6SG, n = 11). After a 2-wk washout period and another 2-wk familiarization period, participants performed a lower-limb training program twice a week for 12 wk. Maximum dynamic strength (1RM) in the barbell back squat, vastus lateralis cross-sectional area, and the sum of lateral thigh muscle thickness at 30%, 50%, and 70% of the femur length were assessed at baseline and after the 12-wk training program. RESULTS: Regarding 1RM, multiple comparisons revealed that 6SG elicited higher muscle strength gains than 4SG ( P = 0.002) and CG ( P < 0.0001), and 4SG had greater improvements than CG ( P = 0.023). Cross-sectional area and sum of lateral thigh muscle thickness showed no between-group differences ( P = 0.067 and P = 0.076, respectively). However, an inspection of 95% confidence intervals suggests a potential dose-response relationship, with results appearing to plateau in the higher volume conditions. CONCLUSIONS: Our results suggest that progressively adding four or six sets per week every 2 wk elicited greater lower-limb strength in resistance-trained individuals over a 12-wk training period. Although our findings indicate a possible small benefit for higher volume conditions regarding hypertrophic adaptations in this population, the limited certainty of our findings warrants caution.

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ABSTRACT: Molinari, T, Radaelli, R, Rech, A, Brusco, CM, Markarian, AM, and Lopez, P. Moderators of resistance training effects in healthy young women: A systematic review and meta-analysis. J Strength Cond Res 38(4): 804-814, 2024-To systematically review and analyze the effects of resistance-based exercise programs and potential moderators of change in body fat percentage, whole-body fat and lean mass, muscle hypertrophy, muscle strength, and muscle power/rapid force in healthy young women (between 18 and 35 years). A systematic search was undertaken in 7 databases from inception to May 2022. Eligible randomized controlled trials examined the effects of resistance-based exercise programs on outcomes of interest in healthy young women. Meta-analysis was undertaken with a 3-level mixed-effects model. Associations between standardized mean difference (SMD) and potential moderators (number of sessions, weekly volume, and intensity) were tested by meta-regression models. Statistical significance was set at an α level of 0.05, whereas an α level of 0.05-0.10 was also considered for potential moderators of resistance training effects. Forty articles ( n = 1,312) were included. Resistance-based exercise programs resulted in a significant improvement of 0.4 SMD (95% confidence intervals [95% CI]: 0.2 to 0.5, p < 0.001) in lean mass/muscle hypertrophy and 1.2 SMD (95% CI: 0.9 to 1.5, p < 0.001) in muscle strength. A higher number of sessions was associated with changes in lean mass/muscle hypertrophy ( ß = 0.01 ± 0.00, p = 0.009), whereas a higher weekly volume approached statistical significance to moderate changes in muscle strength ( ß = 0.01 ± 0.01, p = 0.053). Body fat percentage (-0.4 SMD, 95% CI: -0.6 to -0.1, p = 0.006) and muscle power/rapid force (0.6 SMD, 95% CI: 0.2 to 1.1, p = 0.011) were significantly improved. In conclusion, a higher resistance training volume was associated with greater improvements in lean mass/muscle hypertrophy, muscle strength, and body fat percentage, whereas muscle power/rapid force improvements were observed irrespective of prescription characteristics. These findings may help in designing resistance training programs for muscle hypertrophy, strength and power, and body fat percentage in healthy women.

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OBJECTIVE: To analyze the effects of androgen therapy on the thyroarytenoid (TA) muscle, expression of androgen receptors (ARs) and hyaluronic acid (HA) concentration in the vocal folds (VFs) of adult female rats. METHODS: Twenty-one adult female Wistar rats were divided into experimental and control groups. The experimental group received weekly intramuscular injections of nandrolone decanoate for 9 weeks. Following euthanasia and dissection of the VFs, histomorphometric analysis of the TA muscle, immunohistochemical evaluation of ARs, and measurement of HA concentration using the ELISA-like fluorimetric method were performed. RESULTS: The experimental group exhibited a significantly larger mean fiber cross-sectional area in the TA muscle compared to the control group (434.3 ± 68.6 µm2 versus 305.7 ± 110.1 µm2; p = 0.029), indicating muscle hypertrophy. There was no significant difference in the number of muscle fibers. The experimental group showed higher expression of ARs in the lamina propria (62.0% ± 30.3% versus 22.0% ± 22.8%; p = 0.046) and in the TA muscle (45.0% ± 22.6% versus 18.3% ± 9.8%; p = 0.024). There was no significant difference in the concentration of HA. CONCLUSION: Exposure of adult female rats to androgen therapy resulted in hypertrophy of the TA muscle and increased expression of ARs in the VFs. The TA muscle seems to be the primary target of testosterone action in the VF, and the up-regulation of ARs might contribute to the persistent deepening of the voice. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2316-2321, 2024.

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The bilateral presentation of peritonsillar abscess is uncommon. Its management is controversial and it has been argued whether a quinsy tonsillectomy or an interval tonsillectomy should be performed. Here we describe the case of a 14-year-old boy with sore throat, trismus, and fever. He had bilateral tonsillar hypertrophy, convex arches, and soft palate edema. Computed tomography: bilateral tonsillar hypertrophy, with post-contrast enhancement, both with collection, edema with moderate pharyngeal stenosis. The patient was hospitalized for intravenous therapy and tonsillectomy with bilateral drainage resulting in a complete resolution of his condition and discharge at 48 hours. In the presence of a peritonsillar abscess, an unsuspected contralateral abscess should be considered. It should be diagnosed and managed adequately to prevent complications. Quinsy tonsillectomy could be safe and should be considered in patients who will undergo anesthesia for abscess drainage. The final decision should be made for each patient on an individual basis.

La presentación bilateral del absceso periamigdalino es poco frecuente. Su abordaje es controversial y se discute si realizar amigdalectomía en caliente versus diferida. Se presenta el caso de un paciente de sexo masculino, de 14 años, con odinofagia, trismo y fiebre. Presentaba hipertrofia amigdalina bilateral, pilares abombados y edema de paladar blando. Tomografía computada: hipertrofia amigdalina bilateral, con realce poscontraste, ambas con colección, edema con moderada estenosis faríngea. Se decidió internación para tratamiento endovenoso y amigdalectomía con drenaje bilateral. Resolución completa del cuadro con alta a las 48 horas. Ante la presencia de un absceso periamigdalino, debe considerarse la posibilidad de un absceso contralateral oculto. Debe ser diagnosticado y tratado adecuadamente para prevenir complicaciones. La amigdalectomía en caliente podría ser un tratamiento seguro y debería ser considerado en pacientes que serán sometidos a anestesia para drenaje. La decisión final debe ser determinada para cada caso en particular.

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AIM: To evaluate the effects of resistance exercise training (RET) and/or glutamine supplementation (GS) on signaling protein synthesis in adult rat skeletal muscles. METHODS: The following groups were studied: (1) control, no exercise (C); (2) exercise, hypertrophy resistance exercise training protocol (T); (3) no exercise, supplemented with glutamine (G); and (4) exercise and supplemented with glutamine (GT). The rats performed hypertrophic training, climbing a vertical ladder with a height of 1.1 m at an 80° incline relative to the horizontal with extra weights tied to their tails. The RET was performed three days a week for five weeks. Each training session consisted of six ladder climbs. The extra weight load was progressively increased for each animal during each training session. The G groups received daily L-glutamine by gavage (one g per kilogram of body weight per day) for five weeks. The C group received the same volume of water during the same period. The rats were euthanized, and the extensor digitorum longus (EDL) muscles from both hind limbs were removed and immediately weighed. Glutamine and glutamate concentrations were measured, and histological, signaling protein contents, and mRNA expression analyses were performed. RESULTS: Supplementation with free L-glutamine increased the glutamine concentration in the EDL muscle in the C group. The glutamate concentration was augmented in the EDL muscles from T rats. The EDL muscle mass did not change, but a significant rise was reported in the cross-sectional area (CSA) of the fibers in the three experimental groups. The levels of the phosphorylated proteins (pAkt/Akt, pp70S6K/p70S6K, p4E-BP1/4E-BP1, and pS6/S6 ratios) were significantly increased in EDL muscles of G rats, and the activation of p4E-BP1 was present in T rats. The fiber CSAs of the EDL muscles in T, G, and GT rats were increased compared to the C group. These changes were accompanied by a reduction in the 26 proteasome activity of EDL muscles from T rats. CONCLUSION: Five weeks of GS and/or RET induced muscle hypertrophy, as indicated by the increased CSAs of the EDL muscle fibers. The increase in CSA was mediated via the upregulated phosphorylation of Akt, 4E-BP1, p70S6k, and S6 in G animals and 4E-BP1 in T animals. In the EDL muscles from T animals, a decrease in proteasome activity, favoring a further increase in the CSA of the muscle fibers, was reported.

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BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

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