Aerobic (AE) and resistance exercise (RE) elicit unique adaptations in skeletal muscle that have distinct implications for health and performance. The purpose of this study was to identify the unique transcriptome response of skeletal muscle to acute AE and RE. In a counterbalanced, crossover design, six healthy, recreationally active young men (27 ± 3 yr) completed acute AE (40 min of cycling, ∼70% maximal HR) and RE [8 sets, 10 reps, ∼65% 1-repetition maximum (1RM)], separated by ∼1 wk. Muscle biopsies (vastus lateralis) were obtained before and at 1 and 4 h postexercise. Whole transcriptome RNA sequencing (HiSeq2500; Illumina) was performed on cDNA synthesized from skeletal muscle RNA. Sequencing data were analyzed using HTSeq, and differential gene expression was identified using DESeq2 [adjusted P value (FDR) <0.05, >1.5-fold change from preexercise]. RE resulted in a greater number of differentially expressed genes at 1 (67 vs. 48) and 4 h (523 vs. 221) compared with AE. We identified 348 genes that were differentially expressed only following RE, whereas 48 genes were differentially expressed only following AE. Gene clustering indicated that AE targeted functions related to zinc interaction, angiogenesis, and ubiquitination, whereas RE targeted functions related to transcription regulation, cytokine activity, cell adhesion, kinase activity, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. ESRRG and TNFSRF12A were identified as potential targets related to the specific response of skeletal muscle to AE and RE, respectively. These data describe the early postexercise transcriptome response of skeletal muscle to acute AE and RE and further highlight that different forms of exercise stimulate unique molecular activity in skeletal muscle. NEW & NOTEWORTHY Whole transcriptome RNA sequencing was used to determine the early postexercise transcriptome response of skeletal muscle to acute aerobic (AE) and resistance exercise (RE) in untrained individuals. Although a number of shared genes were stimulated following both AE and RE, several genes were uniquely responsive to each exercise mode. These findings support the need for future research focused to better identify the role of exercise mode as it relates to targeting specific cellular skeletal muscle abnormalities.

Acetaminophen (APAP) given during chronic exercise reduces skeletal muscle collagen and cross-linking in rats. We propose that the effect of APAP on muscle extracellular matrix (ECM) may, in part, be mediated by dysregulation of the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). The purpose of this study was to evaluate the impact of APAP consumption during acute resistance exercise (RE) on several regulators of the ECM in human skeletal muscle. In a double-blinded, placebo-controlled, randomized crossover design, recreationally active men ( = 8, 25 ± 2 yr) performed two trials of knee extension. Placebo (PLA) or APAP (1,000 mg/6 h) was given for 24 h before and immediately following RE. Vastus lateralis biopsies were taken at baseline and 1 and 3 h post-RE. Quantitative RT-PCR was used to determine differences in mRNA expression. MMP-2, type I collagen, and type III collagen mRNA expression was not altered by exercise or APAP ( > 0.05). When compared with PLA, TIMP-1 expression was lower at 1 h post-RE during APAP conditions but greater than PLA at 3 h post-RE ( < 0.05). MMP-9 expression and protein levels were elevated at 3 h post-RE independent of treatment ( < 0.05). Lysyl oxidase expression was greater at 3 h post-RE during APAP consumption ( < 0.05) compared with PLA. MMP-2 and TIMP-1 protein was not altered by RE or APAP ( > 0.05). Phosphorylation of ERK1/2 and p38-MAPK increased ( < 0.05) with RE but was not influenced by APAP. Our findings do not support our hypothesis and suggest that short-term APAP consumption before RE has a small impact on the measured ECM molecules in human skeletal muscle following acute RE.

Several recent investigations have demonstrated that the ability of various tendons to alter structural and functional properties in response to exercise are muted in women compared with men. We hypothesize that this disparity between men and women may be due to a reduced tendon production of key mediators of tendon extracellular matrix (ECM) remodeling in response to mechanical loading, e.g., exercise. Using microdialysis before and after an acute bout of resistance exercise, we evaluated Achilles peritendinous levels of insulin-like growth factor-1 (IGF-1) and interleukin-6 (IL-6), which have both been shown to increase tendon collagen synthesis. Additionally, the matrix remodeling enzymes matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also evaluated. IGF-1 levels were elevated ( < 0.05) to a similar extent in men and women after 3 h of exercise but remained elevated at 4 h in only women. IL-6 levels were ~4-fold greater after exercise in both men and women ( < 0.05). MMP-2 levels increased to a similar extent (~2-3-fold) in men and women ( < 0.05). In contrast, MMP-9 increased with exercise but only in men ( < 0.05). Last, TIMP-1 levels also increased ( < 0.05) with exercise in men and women but the increase was more prolonged in women. In conclusion, we observed modest sex differences in tendon release of MMP-9, TIMP-1, and IGF-1 after acute resistance exercise. If such differences persist throughout a chronic exercise training, they may contribute to the reduced ability of women to adapt to exercise compared with men. In this investigation we utilized microdialysis of the peritendinous Achilles to evaluate potential differences between men and women in tendon production of key regulators of extracellular matrix remodeling. We demonstrate that a modest sex-specific difference exists in peritendinous levels of several key extracellular matrix modulators after an acute bout of 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-rpS6 was increased in both groups but to a greater extent in PLA. At 3 h p-S6K1 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.

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.