Patellar tendon biomechanical and morphologic properties and their relationship to serum clinical variables in persons with prediabetes and type 2 diabetes.

Tendon biomechanical properties and fibril organization are altered in patients with diabetes compared to healthy individuals, yet few biomarkers have been associated with in vivo tendon properties. We investigated the relationships between in vivo imaging-based tendon properties, serum variables, and patient characteristics across healthy controls (n = 14, age: 45 ± 5 years, body mass index [BMI]: 24 ± 1, hemoglobin A1c [HbA1c]: 5.3 ± 0.1%), prediabetes (n = 14, age: 54 ± 5 years, BMI: 29 ± 2; HbA1c: 5.7 ± 0.1), and type 2 diabetes (n = 13, age: 55 ± 3 years, BMI: 33 ± 2, HbA1c: 6.7 ± 0.3). We used ultrasound speckle-tracking and measurements from magnetic resonance imaging (MRI) to estimate the patellar tendon in vivo tangent modulus. Analysis of plasma c-peptide, interleukin-1ß (IL-1ß), IL-6, IL-8, tumor necrosis factor-α (TNF-α), adiponectin, leptin, insulin-like growth factor 1 (IGF-1), and C-reactive protein (CRP) was completed. We built regression models incorporating statistically significant covariates and indicators for the clinically defined groups. We found that tendon cross-sectional area normalized to body weight (BWN CSA) and modulus were lower in patients with type 2 diabetes than in healthy controls (p < 0.05). Our regression analysis revealed that a model that included BMI, leptin, high-density lipoprotein (HDL), low-density lipoprotein (LDL), age, and group explained ~70% of the variability in BWN CSA (R2 = 0.70, p < 0.001). For modulus, including the main effects LDL, groups, HbA1c, age, BMI, cholesterol, IGF-1, c-peptide, leptin, and IL-6, accounted for ~54% of the variability in modulus (R2 = 0.54, p < 0.05). While BWN CSA and modulus were lower in those with diabetes, group was a poor predicter of tendon properties when considering the selected covariates. These data highlight the multifactorial nature of tendon changes with diabetes and suggest that blood variables could be reliable predictors of tendon properties.

ULTRASOUND BIOMICROSCOPY AND ECHOGENIC EXTERNAL MARKER ASSISTED INTRAOCULAR FOREIGN BODY REMOVAL.

PURPOSE: We report a novel method of intraoperative localization of a retained anterior intraocular foreign body (IOFB), using a combination of ultrasound biomicrosopy and an insulated needle. METHODS: A retrospective case report of a 56-year-old man who presented with a right eye IOFB. RESULTS: On presentation, vision was decreased in the right eye to count fingers with a small subconjunctival hemorrhage, but no other signs of a penetrating laceration. Orbital CT revealed an IOFB, and the initial vitrectomy failed to retrieve the IOFB. Then, during the subsequent vitrectomy, using an ultrasound compatible needle and an ultrasound biomicrosopy, we were able to precisely locate and remove the small anterior IOFB. CONCLUSION: Retained IOFBs can lead to severe irreversible vision loss if not promptly removed. Ancillary imaging modalities and localization techniques can help locate occult IOFBs in difficult cases.

Impact of essential amino acid intake, resistance exercise, and aging on the concentration of Achilles peritendinous amino acids and procollagen Iα1 in humans.

Recent studies have shown that consuming amino acid-rich compounds improves tendon collagen content and biomechanical properties. Yet, it is unclear if the consumption of amino acids alters local (peritendinous) amino acid concentrations. If aging or exercise influence local amino acid concentrations in conjunction with an amino acid bolus is also not known. We conducted two studies. In Study 1, young women (n = 7, 25 ± 2 years) completed two identical resistance training sessions with either essential amino acid (EAA) or placebo consumption. In Study 2, an EAA bolus identical to Study 1 was given to younger (n = 7; 27 ± 1 year) and older adults (n = 6; 68 ± 2 years). Microdialysis was used to determine Achilles peritendinous amino acid and pro-collagen Iα1 (a marker of collagen synthesis) concentrations. In Study 1, amino acid consumption increased peritendinous concentrations of all EAA except histidine (p < 0.05). In Study 2, the peritendinous concentration of EAAs except for methionine, histidine, and lysine (p > 0.05) increased with time (p < 0.05). Further, the concentrations of most measured amino acids were greater in older adults (p < 0.05). Pro-collagen Iα1 concentration (p > 0.05) was unaffected by exercise, EAA, or aging (p > 0.05). Our findings demonstrate the following: (1) when not combined with exercise, an oral EAA bolus leads to only modest increases in Achilles peritendinous amino acid concentrations; (2) when combined with resistance exercise, EAA consumption resulted in greater peritendinous amino acid concentrations compared to no exercise; (3) the basal concentrations of most amino acids were greater in older adults, and (4) neither the EAA bolus nor exercise altered peritendinous pro-collagen concentrations.

Symptomatic Hammertoes Treatment Comparison: Peg-in-Hole Arthrodesis Versus End-to-End Screw Fixation.

Proximal interphalangeal (PIP) arthrodesis technique utilizing the peg-in-hole arthrodesis was founded to avoid the use of retained internal fixation implants and thereby potentially decrease the concern of hardware complication. The specific aim of this study was to report the complication rates of the modified peg-in-hole arthrodesis technique and the end-to-end arthrodesis with single screw fixation technique for correcting symptomatic hammertoe deformities in lesser digits. This retrospective chart review included patients who underwent surgical hammertoe correction of lesser digits between the dates of January 2012 and December 2019. Patient demographic data and charts were reviewed to evaluate need for revision including screw/pin removal and complications related to corrective surgery. Five hundred ninety-three symptomatic hammertoe deformity cases (443 female, 150 male) were identified, with 113 cases (88 female, 25 male) treated with peg-in-hole arthrodesis technique and 480 cases (355 female, 125 male) treated with end-to-end arthrodesis with a single screw technique. The deformity recurrence rate was not significantly different between the two techniques (peg-in-hole: 10%, end-to-end: 13%, p = .428). There were 97 cases with postoperative complications that required re-operation (peg-in-hole: 7 cases, end-to-end: 90 cases) with the majority detected at <6 months. There was no statistically significant difference in reoperation rate between the peg-in-hole technique and the end-to-end arthrodesis technique reoperated with reasons excluding simple screw removal (p = .068). This study tended to show these two arthrodesis techniques have equivalent risks and similar success in bone healing; however, the peg-in-hole arthrodesis technique offers an advantage that does not result in retained hardware.

Impact of elevated serum advanced glycation end products and exercise on intact and injured murine tendons.

OVERVIEW: Delayed tendon healing is a significant clinical challenge for those with diabetes. We explored the role of advanced glycation end-products (AGEs), a protein modification present at elevated levels in serum of individuals with diabetes, on injured and intact tendons using a mouse model. Cell proliferation following tissue injury is a vital component of healing. Based on our previous work demonstrating that AGEs limit cell proliferation, we proposed that AGEs are responsible for the delayed healing process commonly observed in diabetic patients. Further, in pursuit of interventional strategies, we suggested that moderate treadmill exercise may support a healing environment in the presence of AGEs as exercise has been shown to stimulate cell proliferation in tendon tissue. MATERIALS AND METHODS: Mice began receiving daily intraperitoneal injections of bovine serum albumin (BSA)-Control or AGE-BSA injections (200µg/ml) at 16-weeks of age. A tendon injury was created in the central third of both patellar tendons. Animals assigned to an exercise group began a moderate treadmill protocol one week following injury. The intact Achilles tendon and soleus muscle were also evaluated to assess the effect of BSA and AGE-BSA on un-injured muscle and tendon. RESULTS: We demonstrate that our injection dosing and schedule lead to an increase in serum AGEs. Our findings imply that AGEs indeed modulate gene expression following a patellar tendon injury and have modest effects on gene expression in intact muscle and tendon. CONCLUSIONS: While additional biomechanical analysis is warranted, these data suggest that elevated serum AGEs in persons with diabetes may impact tendon health.

Bilateral Cystoid Macular Edema Following Bimatoprost Implants.

PURPOSE: To report the development of bilateral cystoid macular edema (CME) following bimatoprost implant (Durysta) injections in both eyes to treat primary open angle glaucoma (POAG). METHODS: Case Report. RESULTS: A 93-year-old woman with a history of POAG received bimatoprost implant (Durysta) injections in both eyes four weeks apart. The patient subsequently developed progressively decreased visual acuity in both eyes due to bilateral CME, which improved with topical corticosteroid therapy. CONCLUSIONS: Bimatoprost implant (Durysta) can cause CME in susceptible individuals. Patients who received the implant should be assessed for the presence of CME following any decline in visual acuity, particularly in high-risk patients.

Descriptive transcriptome analysis of tendon derived fibroblasts following in-vitro exposure to advanced glycation end products.

BACKGROUND: Tendon pathologies affect a large portion of people with diabetes. This high rate of tendon pain, injury, and disease appears to manifest independent of well-controlled HbA1c and fasting blood glucose. Advanced glycation end products (AGEs) are elevated in the serum of those with diabetes. In vitro, AGEs severely impact tendon fibroblast proliferation and mitochondrial function. However, the extent that AGEs impact the tendon cell transcriptome has not been evaluated. OBJECTIVE: The purpose of this study was to investigate transcriptome-wide changes that occur to tendon-derived fibroblasts following treatment with AGEs. We propose to complete a descriptive approach to pathway profiling to broaden our mechanistic understanding of cell signaling events that may contribute to the development of tendon pathology. METHODS: Rat Achilles tendon fibroblasts were treated with glycolaldehyde-derived AGEs (200µg/ml) for 48 hours in normal glucose (5.5mM) conditions. In addition, total RNA was isolated, and the PolyA+ library was sequenced. RESULTS: We demonstrate that tendon fibroblasts treated with 200µg/ml of AGEs differentially express 2,159 gene targets compared to fibroblasts treated with an equal amount of BSA-Control. Additionally, we report in a descriptive and ranked fashion 21 implicated cell-signaling pathways. CONCLUSION: Our findings suggest that AGEs disrupt the tendon fibroblast transcriptome on a large scale and that these pathways may contribute to the development and progression of diabetic tendinopathy. Specifically, pathways related to cell cycle progression and extracellular matrix remodeling were affected in our data set and may play a contributing role in the development of diabetic tendon complications.

Progress in the pharmacotherapy of uveitis: the art of personalized care.

INTRODUCTION: Uveitis is a heterogeneous group of inflammatory intraocular disorders that can lead to blindness, but prompt diagnosis and management can improve visual outcomes and reduce treatment burden. AREAS COVERED: In this review, the authors provide an overview of commonly used treatments for the management of noninfectious uveitis. EXPERT OPINION: Initially, the treatment of noninfectious uveitis was limited to corticosteroids, which have a broad range of adverse ocular and systemic effects. Now new delivery and therapeutic options, such as biological response modulators, represent novel yet exciting additions to this armory and have the potential to alter the course of treatment as well as prognostic outcomes for uveitis patients. Further research is needed to evaluate the efficacy of this novel class of immunomodulators in uveitis therapy.

Asymptomatic Intraosseous Meningioma of the Humerus: A Case Report and Review of the Literature.

Meningiomas are the most common central nervous system tumor. They are typically benign neoplasms but may produce neurological symptoms due to mass effect. Meningiomas may also extend to extradural locations; however, these account for only a small percentage of all meningiomas. Most extradural meningiomas arise in intraosseous locations, usually within the cranial bones or vertebrae. However, this is a rare case of extradural extension of an asymptomatic intracranial meningioma to the proximal humerus in the absence of any musculoskeletal symptoms. To the best of our knowledge, this presentation of an extradural intraosseous meningioma has not previously been reported in the literature. We present a case of an incidental intraosseous meningioma in a 66-year-old man. This patient was initially being screened for metastasis of stage IA1 adenocarcinoma of the lung, and a positron emission tomography (PET) scan revealed a focus of activity in the proximal diaphysis of the right humerus suspicious for malignancy. The upper extremity magnetic resonance imaging (MRI) demonstrated an indeterminate lesion. Curettage of the humeral lesion revealed an intraosseous psammomatous meningioma without evidence of metastatic lung carcinoma. Our case report aims to illustrate the importance of considering alternative metastatic sources, such as intracranial meningioma, during the investigation of an indeterminate bony lesion. This is the first case to illustrate asymptomatic intraosseous meningioma in an appendicular skeletal location, highlighting the need for thorough source investigation.

Lack of Increase in Muscle Mitochondrial Protein Synthesis During the Course of Aerobic Exercise and Its Recovery in the Fasting State Irrespective of Obesity.

Acute aerobic exercise induces skeletal muscle mitochondrial gene expression, which in turn can increase muscle mitochondrial protein synthesis. In this regard, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), is a master regulator of mitochondrial biogenesis, and thus mitochondrial protein synthesis. However, PGC-1α expression is impaired in muscle of humans with obesity in response to acute aerobic exercise. Therefore, we sought to determine whether muscle mitochondrial protein synthesis is also impaired under the same conditions in humans with obesity. To this end, we measured mitochondrial and mixed-muscle protein synthesis in skeletal muscle of untrained subjects with (body fat: 34.7 ± 2.3%) and without (body fat: 25.3 ± 3.3%) obesity in a basal period and during a continuous period that included a 45 min cycling exercise (performed at an intensity corresponding to 65% of heart rate reserve) and a 3-h post-exercise recovery. Exercise increased PGC-1α mRNA expression in muscle of subjects without obesity, but not in subjects with obesity. However, muscle mitochondrial protein synthesis did not increase in either subject group. Similarly, mixed-muscle protein synthesis did not increase in either group. Concentrations of plasma amino acids decreased post-exercise in the subjects without obesity, but not in the subjects with obesity. We conclude that neither mitochondrial nor mixed-muscle protein synthesis increase in muscle of humans during the course of a session of aerobic exercise and its recovery period in the fasting state irrespective of obesity. Trial Registration: The study has been registered within ClinicalTrials.gov (NCT01824173).

Acute-Onset Achilles Tendon Pain and Swelling Treated with an Amniotic Fluid-Derived Allograft: A Case Study.

BACKGROUND: Tendinopathies are common musculoskeletal disorders that often develop because of chronic loading and failed healing. Tendinopathy related to systemic inflammation has been less extensively examined. Furthermore, although the use of biological agents to treat tendinopathies continues to gain popularity, the use of amniotic fluid-derived allografts in outpatient settings to resolve tendinopathies requires further evaluation. METHODS: The focus of this case report is a 25-year-old man who presented for a second opinion, having been diagnosed with Haglund deformity and Achilles tendinopathy. At the time of presentation, he complained of 10 of 10 pain to the right Achilles tendon. He was treating the injury conservatively with intermittent use of a controlled ankle motion boot and working with physiotherapy for approximately 5 months before presentation. Diagnostic ultrasound along with magnetic resonance imaging indicated distal thickening of the Achilles tendon, substantial fluid and edema in the Kager fat pad, and retrocalcaneal erosions with bursitis. Conservative management did not resolve the symptoms. As an alternative to surgery, the patient elected to undergo an Achilles tendon injection of an amniotic fluid-derived allograft. Before and after the initial injection, a microdialysis catheter was inserted into the Achilles peritendinous space to sample local levels of extracellular matrix enzymes and growth factors important for tendon remodeling. The patient received considerable relief with the initial injection, but did not return to full strength. Over the subsequent 8 weeks, the patient was followed closely and was able to return to daily activities with minimal pain. He was not able to return to a more active lifestyle without further Achilles pain, so a second amniotic fluid-derived allograft injection was performed 8 weeks after the initial injection. RESULTS: Injection of the initial allograft resulted in significant improvement, but not complete resolution of pain and swelling. Microdialysis findings suggested a reduction in peritendinous levels of the cytokine interlukin-6 in addition to changes in extracellular matrix regulatory enzymes. After 8 weeks of additional conservative therapy and a second injection, no further improvement in pain was noted. CONCLUSIONS: Based on the clinical improvement of symptoms in this individual and the changes seen with microdialysis methodology, the authors find the use of amniotic fluid-derived allograft injection for treatment of Achilles pain in this patient to be a viable treatment. Additional comorbidities of systemic inflammatory polyarthritis and possible seronegative disease were addressed after rheumatology consultation with a variety of medications that provided the patient additional relief of his symptoms. The patient ultimately moved and was lost to further follow-up.

The Impact of Genistein Supplementation on Tendon Functional Properties and Gene Expression in Estrogen-Deficient Rats.

Tendinopathy risk increases with menopause. The phytoestrogen genistein prevents collagen loss during estrogen deficiency (ovariectomy [OVX]). The influence of genistein on tendon function and extracellular matrix (ECM) regulation is not well known. We determined the impact of genistein on tendon function and the expression of several genes important for the regulation of tendon ECM. Eight-week-old rats (n = 42) were divided into three groups: intact, OVX, or OVX-genistein (6 mg/kg/day) for 6 weeks. Tail fascicles were assessed with a Deben tensile stage. Achilles tendon mRNA expression was determined with digital droplet polymerase chain reaction. Compared to intact, fascicle stress tended to be lower in untreated OVX rats (P = .022). Furthermore, fascicle modulus and energy density were greater in genistein-treated rats (P < .05) compared to intact. Neither OVX nor genistein altered expression of Col1a1, Col3a1, Casp3, Casp8, Mmp1a, Mmp2, or Mmp9 (P > .05). Compared to intact, Tnmd and Esr1 expression were greater and Pcna and Timp1 expression were lower in OVX rats (P < .05). Genistein treatment returned Tnmd, Pcna, and Timp1 to levels of intact-vehicle (P < .05), but did not alter Scx or Esr1 (P > .05). Several ß-catenin/Wnt signaling-related molecules were not altered by OVX or genistein (P > .05). Our findings demonstrate that genistein improves tendon function in estrogen-deficient rats. The effect of genistein in vivo was predominately on genes related to cell proliferation rather than collagen remodeling.

Advanced Glycation End-Products Suppress Mitochondrial Function and Proliferative Capacity of Achilles Tendon-Derived Fibroblasts.

Debilitating cases of tendon pain and degeneration affect the majority of diabetic individuals. The high rate of tendon degeneration persists even when glucose levels are well controlled, suggesting that other mechanisms may drive tendon degeneration in diabetic patients. The purpose of this study was to investigate the impact of advanced glycation end-products on tendon fibroblasts to further our mechanistic understanding of the development and progression of diabetic tendinopathy. We proposed that advanced glycation end-products would induce limitations to mitochondrial function and proliferative capacity in tendon-derived fibroblasts, restricting their ability to maintain biosynthesis of tendon extracellular matrix. Using an in-vitro cell culture system, rat Achilles tendon fibroblasts were treated with glycolaldehyde-derived advanced glycation end-products (0, 50, 100, and 200 µg/ml) for 48 hours in normal glucose (5.5 mM) and high glucose (25 mM) conditions. We demonstrate that tendon fibroblasts treated with advanced glycation end-products display reduced ATP production, electron transport efficiency, and proliferative capacity. These impairments were coupled with alterations in mitochondrial DNA content and expression of genes associated with extracellular matrix remodeling, mitochondrial energy metabolism, and apoptosis. Our findings suggest that advanced glycation end-products disrupt tendon fibroblast homeostasis and may be involved in the development and progression of diabetic tendinopathy.

All-Cause 30-Day Mortality After Surgical Treatment for Head and Neck Squamous Cell Carcinoma in the United States.

OBJECTIVES: Thirty-day (30-day) mortality, a common posttreatment quality metric, is yet to be described following surgery for head and neck squamous cell carcinoma (HNSCC). This study aimed to measure 30-day postoperative mortality in HNSCC and describe clinical/nonclinical factors associated with 30-day mortality. METHODS: In this retrospective cohort study, the National Cancer Database (2004 to 2013) was queried for eligible cases of HNSCC (n=91,858). Adult patients were included who were treated surgically with curative intent for the primary HNSCC, not missing first treatment, survival, and follow-up information. The outcome of interest was all-cause mortality within 30 days of definitive surgery. Clinical and nonclinical factors associated with all-cause 30-day postoperative mortality were estimated using a fully adjusted, multivariable logistic regression, which accounted for time-varying nature of adjuvant therapy. RESULTS: A total of 775 patients died within 30 days of definitive surgery for HNSCC (30-day mortality rate of 0.84%). Thirty-day mortality rate was however up to 2.33% (95% confidence interval [CI], 1.91%-2.75%) depending on comorbidity. In the fully adjusted model, increasing severity of comorbidity was associated with greater odds of 30-day mortality (Charlson-Deyo comorbidity scores of 1: adjusted odds ratio [aOR], 1.43; 95% CI, 1.21-1.69, and of 2+ aOR, 2.55; 95% CI, 2.07-3.14). Odds of 30-day mortality were greater among Medicaid patients (aOR, 1.77; 95% CI, 1.30-2.41), and in patients in neighborhoods with little education (≥ 29% missing high school diploma: aOR, 1.35; 95% CI, 1.02-1.78). CONCLUSIONS: Patients with higher 30-day mortality were those with a greater burden of comorbidities, with little education, and covered by Medicaid.

Prevalence and sociodemographic factors associated with depression among hospitalized patients with head and neck cancer-Results from a national study.

OBJECTIVE: Depression is a significant problem for patients with head and neck cancer (HNC). This study explored the prevalence of and sociodemographic and clinical factors associated with depression, among patients with HNC. METHODS: We performed a retrospective analysis of 71 541 cases of HNC using a national dataset, the Nationwide Inpatient Sample, from 2008 to 2013. Weighted, multivariate logistic regression analysis estimated association between sociodemographic/clinical factors and tumor anatomical site with diagnosis of a major depressive disorder. RESULTS: Overall prevalence of major depressive disorder in HNC was 9.3%; highest prevalence was found in patients with laryngeal cancer (28.5%). Compared with laryngeal cancer, there were lower odds of depression among patients with oral cavity cancer (adjusted odds ratio [aOR] = 0.90; 95% CI, 0.84-0.97) and other anatomic sites (aOR = 0.87; 95% CI, 0.81-0.94), except oropharyngeal cancer (aOR = 1.00; 95% CI, 0.93-1.08). For every unit increase in comorbidities, odds of depression increased by 20% (aOR = 1.20; 95% CI, 1.19-1.23). Sociodemographic factors associated with increased odds of depression included being female (aOR = 1.77; 95% CI, 1.68-1.87), white (aOR = 1.75; 95% CI, 1.59-1.92), and having Medicaid (aOR = 1.09; 95% CI, 1.01-1.19) or Medicare insurance (aOR = 1.19; 95% CI, 1.10-1.27). CONCLUSIONS: Depression odds vary depending on HNC anatomic site, and one in four patients with laryngeal cancer may be depressed. Since depression is prevalent in this survivor cohort, it is important that psychosocial assessment and intervention are integrated into mainstream clinical care for patients with HNC.

Lower Fasted-State but Greater Increase in Muscle Protein Synthesis in Response to Elevated Plasma Amino Acids in Obesity.

OBJECTIVE: Obesity alters protein metabolism in skeletal muscle, but consistent evidence is lacking. This study compared muscle protein synthesis in adults with obesity and in lean controls in the fasted state and during an amino acid infusion. METHODS: Ten subjects with obesity (age: 36 ± 3 years; BMI: 34 ± 1 kg/m2 ) and ten controls (age: 35 ± 3 years; BMI: 23 ± 1 kg/m2 ) received an infusion of L-[2,3,3,4,5,5,5,6,6,6-2 H10 ]leucine (0.15 µmol/kg fat-free mass/min) to measure muscle protein synthesis after an overnight fast and during amino acid infusion. RESULTS: Despite greater muscle mammalian target of rapamycin phosphorylation (P ≤ 0.05), fasted-state mixed-muscle and mitochondrial protein synthesis were lower in subjects with obesity (P ≤ 0.05). However, the change in mixed-muscle protein synthesis during the amino acid infusion was 2.7-fold greater in subjects with obesity (P ≤ 0.05), accompanied by a greater change in S6 kinase-1 phosphorylation (P ≤ 0.05). The change in mitochondrial protein synthesis did not differ between groups (P > 0.05). CONCLUSIONS: Adults with obesity have reduced muscle protein synthesis in the fasted state, but this response is compensated for by a greater change in overall muscle protein synthesis during amino acid infusion.

Streptozotocin-induced diabetes alters transcription of multiple genes necessary for extracellular matrix remodeling in rat patellar tendon.

OVERVIEW: Tendon collagen fibril degradation is commonly seen in tendons of diabetics, but the mechanisms responsible for these changes remain to be elucidated. We have demonstrated that streptozotocin (STZ)-induced diabetes increases tendon cell proliferation and collagen content. In the present study, we evaluated that impact of STZ-induced diabetes on mRNA transcripts involved with collagen fibril organization, extracellular matrix (ECM) remodeling, apoptosis, and proliferation. MATERIALS AND METHODS: Rats were divided into four groups: nondiabetic (control, n = 9), 1 week (acute, n = 8) or 10 weeks of diabetes (chronic, n = 7), and 10 weeks of diabetes with insulin (insulin, n = 8). RNA was isolated from the patellar tendon for determination of mRNA transcripts using droplet digital PCR (ddPCR). RESULTS: Transcripts for Col1a1, Col3a1, Mmp2, Timp1, Scx, Tnmd, Casp3, Casp8, and Ager were lower in acute relative to control and insulin rats (p ≤ 0.05). With the exception of Scx, transcripts for Col1a1, Col3a1, Mmp2, Timp1, Tnmd, Casp3, Casp8, and Ager were also lower in chronic when compared to control (p < 0.05). Transcripts for Col1a1, Col3a1, Mmp2, Timp1, Tnmd, Casp3, Casp8, and Ager were not different between control and insulin (p > 0.05). Transcripts for Dcn, Mmp1a, Mmp9, Pcna, Tgfbr3, Ptgs2, Ptger2, Ptges, and iNos were not altered by diabetes or insulin (p > 0.05). CONCLUSION: Our findings indicated that STZ-induced diabetes results in rapid and large changes in the expression of several genes that are key to ECM remodeling, maintenance, and maturation.

Prior acetaminophen consumption impacts the early adaptive cellular response of human skeletal muscle to resistance exercise.

Resistance exercise (RE) is a powerful stimulus for skeletal muscle adaptation. Previous data demonstrate that cyclooxygenase (COX)-inhibiting drugs alter the cellular mechanisms regulating the adaptive response of skeletal muscle. The purpose of this study was to determine whether prior consumption of the COX inhibitor acetaminophen (APAP) alters the immediate adaptive cellular response in human skeletal muscle after RE. In a double-blinded, randomized, crossover design, healthy young men ( n = 8, 25 ± 1 yr) performed two trials of unilateral knee extension RE (8 sets, 10 reps, 65% max strength). Subjects ingested either APAP (1,000 mg/6 h) or placebo (PLA) for 24 h before RE (final dose consumed immediately after RE). Muscle biopsies (vastus lateralis) were collected at rest and 1 h and 3 h after exercise. Mammalian target of rapamycin (mTOR) complex 1 signaling was assessed through immunoblot and immunohistochemistry, and mRNA expression of myogenic genes was examined via RT-qPCR. At 1 h p-rpS6Ser240/244 was increased in both groups but to a greater extent in PLA. At 3 h p-S6K1Thr389 was elevated only in PLA. Furthermore, localization of mTOR to the lysosome (LAMP2) in myosin heavy chain (MHC) II fibers increased 3 h after exercise only in PLA. mTOR-LAMP2 colocalization in MHC I fibers was greater in PLA vs. APAP 1 h after exercise. Myostatin mRNA expression was reduced 1 h after exercise only in PLA. MYF6 mRNA expression was increased 1 h and 3 h after exercise only in APAP. APAP consumption appears to alter the early adaptive cellular response of skeletal muscle to RE. These findings further highlight the mechanisms through which COX-inhibiting drugs impact the adaptive response of skeletal muscle to exercise. NEW & NOTEWORTHY The extent to which the cellular reaction to acetaminophen impacts the mechanisms regulating the adaptive response of human skeletal muscle to resistance exercise is not well understood. Consumption of acetaminophen before resistance exercise appears to suppress the early response of mTORC1 activity to acute resistance exercise. These data also demonstrate, for the first time, that resistance exercise elicits fiber type-specific changes in the intracellular colocalization of mTOR with the lysosome in human skeletal muscle.