Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.

Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.

Evaluating ChatGPT Responses on Thyroid Nodules for Patient Education.

Background: ChatGPT, an artificial intelligence (AI) chatbot, is the fastest growing consumer application in history. Given recent trends identifying increasing patient use of Internet sources for self-education, we seek to evaluate the quality of ChatGPT-generated responses for patient education on thyroid nodules. Methods: ChatGPT was queried 4 times with 30 identical questions. Queries differed by initial chatbot prompting: no prompting, patient-friendly prompting, 8th-grade level prompting, and prompting for references. Answers were scored on a hierarchical score: incorrect, partially correct, correct, or correct with references. Proportions of responses at incremental score thresholds were compared by prompt type using chi-squared analysis. Flesch-Kincaid grade level was calculated for each answer. The relationship between prompt type and grade level was assessed using analysis of variance. References provided within ChatGPT answers were totaled and analyzed for veracity. Results: Across all prompts (n = 120 questions), 83 answers (69.2%) were at least correct. Proportions of responses that were at least partially correct (p = 0.795) and correct (p = 0.402) did not differ by prompt; responses that were correct with references did (p < 0.0001). Responses from 8th-grade level prompting were the lowest mean grade level (13.43 ± 2.86) and were significantly lower than no prompting (14.97 ± 2.01, p = 0.01) and prompting for references (16.43 ± 2.05, p < 0.0001). Prompting for references generated 80/80 (100%) of referenced medical publications within answers. Seventy references (87.5%) were legitimate citations, and 58/80 (72.5%) provided accurately reported information from the referenced publication. Conclusion: ChatGPT overall provides appropriate answers to most questions on thyroid nodules regardless of prompting. Despite targeted prompting strategies, ChatGPT reliably generates responses corresponding to grade levels well-above accepted recommendations for presenting medical information to patients. Significant rates of AI hallucination may preclude clinicians from recommending the current version of ChatGPT as an educational tool for patients at this time.

Evaluating ChatGPT responses on obstructive sleep apnea for patient education.

STUDY OBJECTIVES: We evaluated the quality of ChatGPT responses to questions on obstructive sleep apnea for patient education and assessed how prompting the chatbot influences correctness, estimated grade level, and references of answers. METHODS: ChatGPT was queried 4 times with 24 identical questions. Queries differed by initial prompting: no prompting, patient-friendly prompting, physician-level prompting, and prompting for statistics/references. Answers were scored on a hierarchical scale: incorrect, partially correct, correct, correct with either statistic or referenced citation ("correct+"), or correct with both a statistic and citation ("perfect"). Flesch-Kincaid grade level and citation publication years were recorded for answers. Proportions of responses at incremental score thresholds were compared by prompt type using chi-squared analysis. The relationship between prompt type and grade level was assessed using analysis of variance. RESULTS: Across all prompts (n = 96 questions), 69 answers (71.9%) were at least correct. Proportions of responses that were at least partially correct (P = .387) or correct (P = .453) did not differ by prompt; responses that were at least correct+ (P < .001) or perfect (P < .001) did. Statistics/references prompting provided 74/77 (96.1%) references. Responses from patient-friendly prompting had a lower mean grade level (12.45 ± 2.32) than no prompting (14.15 ± 1.59), physician-level prompting (14.27 ± 2.09), and statistics/references prompting (15.00 ± 2.26) (P < .0001). CONCLUSIONS: ChatGPT overall provides appropriate answers to most questions on obstructive sleep apnea regardless of prompting. While prompting decreases response grade level, all responses remained above accepted recommendations for presenting medical information to patients. Given ChatGPT's rapid implementation, sleep experts may seek to further scrutinize its medical literacy and utility for patients. CITATION: Campbell DJ, Estephan LE, Mastrolonardo EV, Amin DR, Huntley CT, Boon MS. Evaluating ChatGPT responses on obstructive sleep apnea for patient education. J Clin Sleep Med. 2023;19(12):1989-1995.

Recovery Benefit With Total Intravenous Anesthesia in Patients Receiving Rhinoplasty.

OBJECTIVE: The aim was to evaluate the difference in recovery when comparing total intravenous anesthesia (TIVA) to inhalational gas anesthesia in patients receiving rhinoplasty. STUDY DESIGN: Retrospective review. SETTING: Postoperative anesthesia care unit (PACU). METHODS: Patients who received a functional or cosmetic rhinoplasty at a single academic institution between April 2017 and November 2020 were included. Inhalational gas anesthesia was in the form of sevoflurane. Phase I recovery time, which was defined as the time it took a patient to reach ≥9/10 on the Aldrete scoring system was recorded, as well as the usage of pain medication in the PACU. The postoperative course and incidence of postoperative nausea and vomiting (PONV) were also collected. RESULTS: Two hundred and two patients were identified with 149 (73.76%) who received TIVA and 53 (26.24%) who received sevoflurane. For the patients who received TIVA, the average recovery time was 101.44 minutes (standard deviation [SD]: 34.64) compared to an average recovery time of 121.09 minutes (SD: 50.19) for patients who received sevoflurane leading to a difference of 19.65 minutes (p = 0.002). Patients who received TIVA experienced less PONV (p = 0.001). There were no differences in the postoperative course including surgical or anesthesia complications, postoperative complications, hospital or Emergency Department admissions, or administration of pain medication (p > 0.05 for all). CONCLUSION: When utilizing TIVA over inhalational anesthesia, patients undergoing rhinoplasty had significantly increased benefits in terms of reduced phase I recovery times and decreased incidence of PONV. TIVA was demonstrated to be a safe and efficacious method of anesthesia for this patient population.

Total Intravenous Anesthesia Versus Inhaled Sevoflurane in Obstructive Sleep Apnea Surgery: A Randomized Controlled Trial.

OBJECTIVE: Specific guidelines regarding an optimal general anesthesia (GA) approach to obstructive sleep apnea (OSA) patients remain undefined. Literature comparing the efficacy of total intravenous anesthesia (TIVA) and inhalational anesthesia in this population is sparse. We hypothesize that OSA patients receiving TIVA will experience reduced recovery times and other improved post-surgical outcomes. STUDY DESIGN: Randomized controlled trial. METHODS: Adult OSA patients undergoing upper airway surgery (hypoglossal nerve stimulation [HNS], nasal, or palate surgery) from February 2020-December 2020 were included. A post-anesthesia care unit (PACU) nursing survey documented patients' alertness, pain, oxygen supplementation, and postoperative nausea and vomiting from PACU arrival to 2 hours. Perioperative timepoints from the electronic medical record (EMR) and a nurse-estimated Phase I recovery time were collected. RESULTS: One hundred eleven patients were included (46 TIVA and 65 inhalational anesthesia). Per EMR-recorded timepoints, TIVA patients undergoing HNS and palate surgery experienced Phase I Time reductions of 12.5 min (p = 0.042) and 27.5 min (p = 0.016), respectively. Per the PACU survey, TIVA patients undergoing any surgery, HNS, or palate surgery experienced nurse-estimated Phase I Time reductions of 16.5 min (p = 0.004), 12.5 min (p = 0.031), and 38.5 min (p = 0.024), respectively. Overall, TIVA patients experienced higher alertness and pain ratings, and lower oxygen supplementation requirements from PACU arrival to 30 min (p < 0.05). CONCLUSION: Patients with OSA receiving TIVA for GA maintenance during upper airway procedures experienced reduced recovery times and oxygen supplementation requirements, and a more rapid return to alertness. Future work toward developing optimized anesthetic guidelines for OSA patients is merited. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:984-992, 2023.

Assessing Postoperative Recovery With Volatile Gas Versus Total Intravenous Anesthesia in Patients With and Without Obstructive Sleep Apnea.

INTRODUCTION: To determine if there is a recovery time difference between patients with and without obstructive sleep apnea (OSA) when using total intravenous anesthesia (TIVA) compared to volatile gas inhalational anesthesia. PATIENTS AND METHODS: OSA and Non-OSA patients were identified at a tertiary institution between January 2019 and November 2020. Non-OSA patients were defined as those who have not been formerly diagnosed with OSA. A modified STOP-BANG score (MSBS) was performed to screen Non-OSA patients for OSA. Recovery was measured by Phase I recovery time, or time it took a patient to reach ≥9/10 on the Aldrete scoring system. RESULTS: A total of 334 patients were included with 142 in the OSA cohort (59 TIVA, 83 inhalational anesthesia) and 192 in the Non-OSA cohort (119 TIVA, 73 inhalational anesthesia). In OSA patients, there was a 41.29-minute recovery time reduction when using TIVA versus sevoflurane (P < .0001). Non-OSA patients recovered faster than OSA patients when undergoing inhalational anesthesia by 46.76 minutes and TIVA by 18.58 minutes (P < .0001 and P = .0907, respectively). Non-OSA patients with a MSBS < 3 and ≥3 had a shorter recovery time compared to OSA patients when both underwent sevoflurane anesthesia (57.27 minutes, P < .0001 and 56.23 minutes, P = .040, respectively). Non-OSA patients with a MSBS of <3 had a decrease in recovery time of 26.68 minutes when compared to OSA patients who underwent TIVA (P = .0004). CONCLUSIONS: When utilizing TIVA over inhalational anesthesia, patients with OSA have significantly increased benefit in terms of reduced Phase I recovery times as compared to Non-OSA patients.

Cost of Total Intravenous Anesthesia Versus Inhalation Anesthesia in Obstructive Sleep Apnea Surgery.

OBJECTIVES: To compare cost and time spent in surgical and postoperative courses in patients with obstructive sleep apnea (OSA) undergoing surgery with either total intravenous anesthesia (TIVA) or inhalational anesthesia. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective review on patients undergoing surgery for OSA under general anesthesia from January 2019 to October 2020. Cost per service was acquired for the day of surgery. RESULTS: A total of 230 patients were included: 95 received TIVA; 135 received inhalation anesthesia. Total cost was significantly higher in the TIVA nasal surgery group by $286 (P = .035). TIVA produced significantly higher pharmacy and operating room costs across all surgeries and OSA severities. These increased costs were offset by significantly lower supply costs in upper airway stimulator (UAS, -$419.50; P = .007) and uvulopalatopharyngoplasty (UPPP, -$115.16; P = .015) patients receiving TIVA. In the TIVA cohort, there was a trend toward lower recovery room costs after UAS (-$111.09; P = .063) and nasal surgery (-$64.45; P = .096) and anesthesia costs after nasal surgery (-$36.67; P = .054). Total recovery time was reduced by 18 minutes (P = .004) for nasal surgery, 25 minutes (P = .043) for UAS, and 27 minutes (P = .147) for UPPP patients receiving TIVA. CONCLUSION: When used in an outpatient setting for patients with OSA, TIVA adds to pharmacy and operating room costs, but this is usually offset by lower supply, anesthesia, and recovery room costs. We found decreased recovery times in the TIVA cohort. TIVA has proven benefits in patient outcomes and can be cost-effective in OSA surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1487-1494, 2022.

Two-Incision Approach for Hypoglossal Nerve Stimulator Placement: A Single Institution Assessment.

OBJECTIVE(S): Upper airway stimulator (UAS) placement is a treatment for obstructive sleep apnea (OSA) with few complications and low morbidity. UAS placement has traditionally been performed using a three-incision approach, however, it has been implanted using a two-incision approach. This approach could significantly decrease operation time without a difference in postoperative complications, demonstrating its safety and feasibility for UAS placement. The objective was to assess operative time and complication rate in the two-incision approach for UAS placement compared to the three-incision approach. STUDY DESIGN: Retrospectively reviewed. METHODS: Patients who underwent UAS placement using the two- or three-incision approach at a single academic institution from November 2014 to June 2021 were retrospectively reviewed. The two-incision approach did not include the incision at the mid-axillary line. Main outcome measures included operation time and complication rates. RESULTS: Three-hundred forty-eight patients underwent UAS placement. The three-incision approach demonstrated an average operation time of 143.3 minutes whereas the two-incision approach averaged 129.4 minutes (P < .001). There was no significant difference in rate of postoperative complications between the two- and three-incision cohorts including pneumothorax (0% vs. 0.4%, P > .99), patient-reported discomfort (5.6% vs. 6.5%, P > .99), activity restriction (0% vs. 1.4%, P > .50), and incisional pain (0.0% vs. 1.0%, P > .99). No patients experienced incision site bleeding or infection. The two-incision approach was associated with decreased rate of revision surgery (0.0% vs. 5.4%, P = .048). CONCLUSION: The UAS two-incision approach proved to have a significantly shorter operative time without an increase in complications as compared to the three-incision approach. This approach is a safe and feasible option. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1687-1691, 2022.

Reduced gastroesophageal reflux disease symptom severity following upper airway surgery for comorbid obstructive sleep apnea.

PURPOSE: To evaluate patient-reported quality of life pertaining to gastroesophageal reflux disease symptoms in patients undergoing upper airway surgery for comorbid obstructive sleep apnea. MATERIALS AND METHODS: A prospective survey-based study was conducted on patients with gastroesophageal reflux disease and comorbid obstructive sleep apnea receiving surgery from July 2020-December 2020. Patients completed the Gastroesophageal Reflux Disease-Health Related Quality of Life Questionnaire at two time-points: one week before surgery and at 6 months following surgery. Disease-related symptoms were rated from 0 (no symptoms) to 5 (incapacitating symptoms). Patient survey scores, demographics, medications, and sleep study parameters were collected for analysis. A p-value <0.05 indicated statistical significance. RESULTS: Twenty-two patients completed the baseline preoperative and 6-month postoperative questionnaires. Median baseline vs. 6-month survey scores significantly decreased for symptoms including heartburn in general (3.0 vs. 2.0, p = 0.006), when lying down (2.5 vs. 1.5, p = 0.046), when standing (2.0 vs 1.0, p = 0.003), following meals (2.0 vs. 2.0, p = 0.042), and cumulative survey score (15.5 vs. 11.0, p = 0.029). Heartburn altering diet or sleep, odynophagia, dysphagia, and medication burden did not change following surgery (p > 0.05). More patients were satisfied with their postoperative condition compared to baseline, however this did not reach statistical significance (40.9% vs. 18.2%, p = 0.18). CONCLUSIONS: Our results suggest that upper airway surgery to treat obstructive sleep apnea may have a positive impact on patient-reported symptoms of gastroesophageal reflux disease, and further investigation into the role of surgery in this setting for improvement of both quality of life and true clinical disease severity is merited.

Upper airway stimulation: Fewer complications, ED presentations, readmissions, and increased surgical success.

OBJECTIVES: Evaluate the rate of complications, readmissions, emergency department presentations, and surgical success rates amongst three standard surgical treatment options for obstructive sleep apnea: upper airway stimulation, transoral robotic surgery, and expansion sphincter pharyngoplasty. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary care center. METHODS: Patients were included who were aged ≥18 years old and underwent upper airway stimulation, transoral robotic surgery, or expansion sphincter pharyngoplasty between January 2011 and May 2020. RESULTS: 345 patients were identified: 58% (n = 201) underwent upper airway stimulation, 10% (n = 35) underwent transoral robotic surgery, and 32% (n = 109) patients underwent expansion sphincter pharyngoplasty. There were 22 emergency department presentations and 19 readmissions, most of which were experienced by patients receiving transoral robotic surgery (six emergencies, seven readmissions) and expansion sphincter pharyngoplasty (12 emergencies, 11 readmissions). Patients with upper airway stimulation had four emergencies and one readmission. Only 2% of the upper airway stimulation cohort had a complication, whereas this was 20% and 12% for the transoral robotic surgery and expansion sphincter pharyngoplasty cohorts, respectively. Patients experienced the highest surgical success rate with upper airway stimulation (69%), whereas patients who received transoral robotic surgery and expansion sphincter pharyngoplasty had success rates of 50% and 51%, respectively. CONCLUSION: Treating obstructive sleep apnea with upper airway stimulation led to lower rates of complications, emergency department presentations, and readmissions in this series. In those for whom upper airway stimulation is appropriate, it may be more effective in successfully treating obstructive sleep apnea than transoral robotic surgery and expansion sphincter pharyngoplasty.

Matrix stiffening induces a pathogenic QKI-miR-7-SRSF1 signaling axis in pulmonary arterial endothelial cells.

Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA-binding protein quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness upregulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine-rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally upregulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from patients with PAH and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, whereas forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

Reduced Recovery Times with Total Intravenous Anesthesia in Patients with Obstructive Sleep Apnea.

OBJECTIVES/HYPOTHESIS: There is currently no standard of care in terms of anesthesia modality for patients receiving upper airway surgery with comorbid obstructive sleep apnea (OSA). Although both total intravenous anesthesia (TIVA) and volatile gas anesthesia are commonly utilized in ambulatory otolaryngology surgery, it is currently unclear if there are any advantages with one modality over the other. We hypothesize that patients receiving upper airway surgery with comorbid OSA will have quicker recovery times with TIVA. STUDY DESIGN: Retrospective chart review from January 2019 to December 2019. METHODS: All patients aged 18 and older receiving upper airway surgery (upper airway stimulation, nasal surgery, modified uvulopalatopharyngoplasty) were included. Patients were excluded when there was incomplete or missing data in the electronic medical record. RESULTS: Eighty-six patients received gas anesthesia and 62 patients received TIVA. Phase I recovery times were significantly reduced by surgery and by severity of OSA: nasal surgery, upper airway stimulation, and modified uvulopalatopharyngoplasty had a reduction of 35.5 minutes (P < .001), 42.5 minutes (P < .001), and 36 minutes (P = .022), respectively. In terms of severity, mild, moderate, and severe OSA had reductions of 23.5 minutes (P = .004), 52 minutes (P = .004), and 47 minutes (P < .001), respectively. The severity of OSA generally correlated with increased time spent in Phase I: as severity increased, Phase I time increased by 16.8 minutes for the gas cohort (P < .001), whereas in the TIVA cohort, it increased only 4.3 minutes (P = .489). CONCLUSION: Patients having upper airway surgery with comorbid OSA that received TIVA (propofol and remifentanil) spent significantly less time in Phase I and the recovery room overall compared to those receiving volatile gas anesthesia in the form of sevoflurane, and this correlated with the severity of OSA. LEVEL OF EVIDENCE: 3. Laryngoscope, 131:925-931, 2021.

Preferential use of total intravenous anesthesia in ambulatory otolaryngology surgery during the COVID-19 pandemic.

The novel coronavirus (SARS-CoV-2 or COVID-19) pandemic has impacted nearly every aspect of otolaryngologic practice. The transition from office-based evaluation to telemedicine and the number of postponed elective surgical cases is unprecedented. There is a significant need to resume elective surgical care for these patients at the appropriate time. As practices begin to move towards resuming elective and same day ambulatory surgery, safety of both the patient and healthcare team is of paramount importance. Usage of total intravenous anesthesia (propofol and remifentanil) over volatile gas anesthesia (e.g., sevoflurane) may increase the number of patients able to safely receive care by reducing potential spread of the virus through reduction in coughing and significantly decreasing the time spent in the recovery room.

Distinct plasma gradients of microRNA-204 in the pulmonary circulation of patients suffering from WHO Groups I and II pulmonary hypertension.

Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06-0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups ( P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 ( P = 0.0004), and a converse increase of extracellular miR-204 ( P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.

Specific circulating microRNAs display dose-dependent responses to variable intensity and duration of endurance exercise.

Circulating microRNAs (c-miRNAs), plasma-based noncoding RNAs that control posttranscriptional gene expression, mediate processes that underlie phenotypical plasticity to exercise. The relationship and biological relevance between c-miRNA expression and variable dose exercise exposure remains uncertain. We hypothesized that certain c-miRNAs respond to changes in exercise intensity and/or duration in a dose-dependent fashion. Muscle release of such c-miRNAs may then deplete intracellular stores, thus facilitating gene reprogramming and exercise adaptation. To address these hypotheses, healthy men participated in variable intensity ( n = 12, 30 × 1 min at 6, 7, and 8 miles/h, order randomized) and variable duration ( n = 14, 7 × 1 mile/h for 30, 60, and 90 min, order randomized) treadmill-running protocols. Muscle-enriched c-miRNAs (i.e., miRNA-1 and miRNA-133a) and others with known relevance to exercise were measured before and after exercise. c-miRNA responses followed three profiles: 1) nonresponsive (miRNA-21 and miRNA-210), 2) responsive to exercise at some threshold but without dose dependence (miRNA-24 and miRNA-146a), and 3) responsive to exercise with dose dependence to increasing intensity (miRNA-1) or duration (miRNA-133a and miRNA-222). We also studied aerobic exercise-trained mice, comparing control, low-intensity (0.5 km/h), or high-intensity (1 km/h) treadmill-running protocols over 4 wk. In high- but not low-intensity-trained mice, we found increased plasma c-miR-133a along with decreased intracellular miRNA-133a and increased serum response factor, a known miR-133a target gene, in muscle. Characterization of c-miRNAs that are dose responsive to exercise in humans and mice supports the notion that they directly mediate physiological adaptation to exercise, potentially through depletion of intracellular stores of muscle-specific miRNAs. NEW & NOTEWORTHY In this study of humans and mice, we define circulating microRNAs in plasma that are dose responsive to exercise. Our data support the notion that these microRNAs mediate physiological adaptation to exercise potentially through depletion of intracellular stores of muscle-specific microRNAs and releasing their inhibitory effects on target gene expression.