Eccentric Exercise as a Potent Prescription for Muscle Weakness After Joint Injury.

Lengthening contractions (i.e., eccentric contractions) are capable of uniquely triggering the nervous system and signaling pathways to promote tissue health/growth. This mode of exercise may be particularly potent for patients suffering from muscle weakness after joint injury. Here we provide a novel framework for eccentric exercise as a safe, effective mode of exercise prescription for muscle recovery.

Breast Implant-associated Anaplastic Large Cell Lymphoma: An Evidence-based Systematic Review.

OBJECTIVE: This evidence-based systematic review synthesizes and critically appraises current clinical recommendations and advances in the diagnosis and treatment of BIA-ALCL. This review also aims to broaden physician awareness across diverse specialties, particularly among general practitioners, breast surgeons, surgical oncologists, and other clinicians who may encounter patients with breast implants in their practice. BACKGROUND: BIA-ALCL is an emerging and treatable immune cell cancer definitively linked to textured-surface breast implants. Although the National Comprehensive Cancer Network (NCCN) consensus guidelines and other clinical recommendations have been established, the evidence supporting these guidelines has not been systematically studied. The purpose of this evidence-based systematic review is to synthesize and critically appraise current clinical guidelines and recommendations while highlighting advances in diagnosis and treatment and raising awareness for this emerging disease. METHODS: This evidence-based systematic review evaluated primary research studies focusing on the diagnosis and treatment of BIA-ALCL that were published in PubMed, Google Scholar, and other scientific databases through March 2020. RESULTS AND CONCLUSIONS: The clinical knowledge of BIA-ALCL has evolved rapidly over the last several years with major advances in diagnosis and treatment, including en bloc resection as the standard of care. Despite a limited number of high-quality clinical studies comprised mainly of Level III and Level V evidence, current evidence aligns with established NCCN consensus guidelines. When diagnosed and treated in accordance with NCCN guidelines, BIA-ALCL carries an excellent prognosis.

Massage as a Mechanotherapy for Skeletal Muscle.

Massage is anecdotally associated with many health benefits, but physiological and clinically relevant mechanisms recently have begun to be investigated in a controlled manner. Herein, we describe research supporting our hypothesis that massage can be used as a mechanotherapy imparting biologically relevant adaptations in skeletal muscle and improving muscle properties.

Serum extracellular vesicle miR-203a-3p content is associated with skeletal muscle mass and protein turnover during disuse atrophy and regrowth.

Small noncoding microRNAs (miRNAs) are important regulators of skeletal muscle size, and circulating miRNAs within extracellular vesicles (EVs) may contribute to atrophy and its associated systemic effects. The purpose of this study was to understand how muscle atrophy and regrowth alter in vivo serum EV miRNA content. We also associated changes in serum EV miRNA with protein synthesis, protein degradation, and miRNA within muscle, kidney, and liver. We subjected adult (10 mo) F344/BN rats to three conditions: weight bearing (WB), hindlimb suspension (HS) for 7 days to induce muscle atrophy, and HS for 7 days followed by 7 days of reloading (HSR). Microarray analysis of EV miRNA content showed that the overall changes in serum EV miRNA were predicted to target major anabolic, catabolic, and mechanosensitive pathways. MiR-203a-3p was the only miRNA demonstrating substantial differences in HS EVs compared with WB. There was a limited association of EV miRNA content to the corresponding miRNA content within the muscle, kidney, or liver. Stepwise linear regression demonstrated that EV miR-203a-3p was correlated with muscle mass and muscle protein synthesis and degradation across all conditions. Finally, EV miR-203a-3p expression was significantly decreased in human subjects who underwent unilateral lower limb suspension (ULLS) to induce muscle atrophy. Altogether, we show that serum EV miR-203a-3p expression is related to skeletal muscle protein turnover and atrophy. We suggest that serum EV miR-203a-3p content may be a useful biomarker and future work should investigate whether serum EV miR-203a-3p content is mechanistically linked to protein synthesis and degradation.

The Effectiveness of Nonoperative Treatment for Anterior Cruciate Ligament Rupture on Patient-Reported Outcomes and Muscular Strength: A Critically Appraised Topic.

Clinical Scenario: Anterior cruciate ligament (ACL) ruptures are one of the most common injuries in young athletic populations. The leading treatment for these injuries is ACL reconstruction (ACL-r); however, nonoperative treatments are also utilized. Following ACL-r, patients experience prolonged muscle weakness and atrophy of the quadriceps muscle group, regardless of rehabilitation. Nonoperative treatment plans following ACL injury exist, but their outcomes are less familiar, in spite of providing insight as a nonsurgical "control" for postsurgical rehabilitation outcomes. Therefore, the purpose of this critically appraised topic was to evaluate quadriceps strength and function following nonoperative ACL rehabilitation using objective and subjective measures including isokinetic dynamometry, the single-leg hop test, and the International Knee Documentation Committee (IKDC) subjective knee form. Focused Clinical Question: What are the effects of nonoperative treatment on peak isokinetic knee-extensor torque, the single-leg hop tests, and the IKDC in patients who have sustained an ACL rupture? Summary of Key Findings: Patients who underwent nonsurgical ACL treatment produced limb symmetry index, with the side-to-side torque difference expressed as a percentage, and values at or above 90% for all 4 single-leg hop tests and strength tests similar to ACL-r patients. All studies showed individuals had higher IKDC scores at baseline collection when compared with patients who underwent ACL-r but showed lower IKDC scores at long-term follow-up compared with ACL-r patients. Clinical Bottom Line: Nonoperative treatments of ACL injuries yield similar long-term results in quadriceps strength as ACL-r. Due to the quality of evidence and the absence of randomized controlled trials on this topic, these outcomes should be considered with caution. Strength of Recommendation: The Oxford Centre for Evidence-Based Medicine taxonomy recommends a grade of B for level 2 evidence with consistent findings.

Appalachian Status Is a Negative Predictor of Breast Reconstruction Following Breast Cancer Resection.

BACKGROUND: Health care disparities in Appalachia are well documented. However, no previous studies have examined possible differences in the utilization of breast reconstruction (BR) in Appalachia. This study aims to determine if a disparity in BR utilization exists in women from Appalachia Kentucky. METHODS: A retrospective, population-based cohort study was conducted from January 1, 2006, to December 31, 2015. The Kentucky Cancer Registry was queried to identify population-level data for female patients diagnosed with breast cancer and treated with mastectomy. A multivariate logistic regression model controlling for patient, disease, and treatment characteristics was constructed to predict the likelihood of BR. RESULTS: Bivariate testing showed differences (P < 0.0001) in BR utilization between Appalachian and non-Appalachian women in Kentucky (15.0% and 26.3%, respectively). Multivariate analysis showed that women from Appalachia (odds ratio, 0.54; confidence interval (95), 0.48-0.61; P < 0.0001) were less likely to undergo BR than non-Appalachian women. Interestingly, the rate of BR increased over time in both Appalachian (r = 0.115; P < 0.0001) and non-Appalachian women (r = 0.148; P < 0.0001). CONCLUSIONS: Despite the benefits of BR, women from Appalachia undergo BR at lower rates and are less likely to receive BR than non-Appalachian Kentuckians. Although the rates of BR increased over time in both populations, access to comprehensive breast cancer care remains a challenge for women from Kentucky's Appalachian region.

Enhanced skeletal muscle regrowth and remodelling in massaged and contralateral non-massaged hindlimb.

KEY POINTS: Muscle fibre cross sectional area is enhanced with massage in the form of cyclic compressive loading during regrowth after atrophy. Massage enhances protein synthesis of the myofibrillar and cytosolic, but not the mitochondrial fraction, in muscle during regrowth. Focal adhesion kinase activation and satellite cell number are elevated in muscles undergoing massage during regrowth. Muscle fibre cross sectional area and protein synthesis of the myofibrillar fraction, but not DNA synthesis, are elevated in muscle of the contralateral non-massaged limb. Massage in the form of cyclic compressive loading is a potential anabolic intervention during muscle regrowth after atrophy. ABSTRACT: Massage, in the form of cyclic compressive loading (CCL), is associated with multiple health benefits, but its potential anabolic effect on atrophied muscle has not been investigated. We hypothesized that the mechanical activity associated with CCL induces an anabolic effect in skeletal muscle undergoing regrowth after a period of atrophy. Fischer-Brown Norway rats at 10 months of age were hindlimb unloaded for a period of 2 weeks. The rats were then allowed reambulation with CCL applied at a 4.5 N load at 0.5 Hz frequency for 30 min every other day for four bouts during a regrowth period of 8 days. Muscle fibre cross sectional area was enhanced by 18% with massage during regrowth compared to reloading alone, and this was accompanied by elevated myofibrillar and cytosolic protein as well as DNA synthesis. Focal adhesion kinase phosphorylation indicated that CCL increased mechanical stimulation, while a higher number of Pax7+ cells likely explains the elevated DNA synthesis. Surprisingly, the contralateral non-massaged limb exhibited a comparable 17% higher muscle fibre size compared to reloading alone, and myofibrillar protein synthesis, but not DNA synthesis, was also elevated. We conclude that massage in the form of CCL induces an anabolic response in muscles regrowing after an atrophy-inducing event. We suggest that massage can be used as an intervention to aid in the regrowth of muscle lost during immobilization.

Shifting the Current Clinical Perspective: Isolated Eccentric Exercise as an Effective Intervention to Promote the Recovery of Muscle After Injury.

Eccentric exercise is able to mechanically engage muscle, initiating strain-sensing molecules that promote muscle recovery by inducing beneficial adaptations in neural activity and muscle morphology, 2 critical components of muscle function that are negatively altered after injury. However, due to misinterpreted mathematic modeling and in situ and in vitro stretch protocols, a dogma that exposing muscle to eccentric exercise is associated with injury has been perpetuated in the literature. In response, clinicians have been biased toward using concentric exercise postinjury to improve the recovery of muscle function. Unfortunately, this conventional approach to rehabilitation does not restore muscle function, and reinjury rates remain high. Here, the authors present experimental evidence and theoretical support for the idea that isolated eccentric exercise is ideally suited to combat muscle inhibition and muscle strains and is an attractive alternative to concentric exercise.

Effectiveness of a Home-Based Eccentric-Exercise Program on the Torque-Angle Relationship of the Shoulder External Rotators: A Pilot Study.

CONTEXT: The role of the rotator cuff is to provide dynamic stability to the glenohumeral joint. Human and animal studies have identified sarcomerogenesis as an outcome of eccentric training indicated by more torque generation with the muscle in a lengthened position. OBJECTIVE: The authors hypothesized that a home-based eccentric-exercise program could increase the shoulder external rotators' eccentric strength at terminal internal rotation (IR). DESIGN: Prospective case series. SETTING: Clinical laboratory and home exercising. PARTICIPANTS: 10 healthy subjects (age 30 ± 10 y). INTERVENTION: All participants performed 2 eccentric exercises targeting the posterior shoulder for 6 wk using a home-based intervention program using side-lying external rotation (ER) and horizontal abduction. MAIN OUTCOME MEASURES: Dynamic eccentric shoulder strength measured at 60°/s through a 100° arc divided into 4 equal 25° arcs (ER 50-25°, ER 25-0°, IR 0-25°, IR 25-50°) to measure angular impulse to represent the work performed. In addition, isometric shoulder ER was measured at 5 points throughout the arc of motion (45° IR, 30° IR, 15° IR, 0°, and 15° ER). Comparison of isometric and dynamic strength from pre- to posttesting was evaluated with a repeated-measure ANOVA using time and arc or positions as within factors. RESULTS: The isometric force measures revealed no significant differences between the 5 positions (P = .56). Analysis of the dynamic eccentric data revealed a significant difference between arcs (P = .02). The percentage-change score of the arc of IR 25-50° was found to be significantly greater than that of the arc of IR 0-25° (P = .007). CONCLUSION: After eccentric training the only arc of motion that had a positive improvement in the capacity to absorb eccentric loads was the arc of motion that represented eccentric contractions at the longest muscle length.

Intrinsic muscle clock is necessary for musculoskeletal health.

KEY POINTS: The endogenous molecular clock in skeletal muscle is necessary for maintenance of phenotype and function. Loss of Bmal1 solely from adult skeletal muscle (iMSBmal1(-/-) ) results in reductions in specific tension, increased oxidative fibre type and increased muscle fibrosis with no change in feeding or activity. Disruption of the molecular clock in adult skeletal muscle is sufficient to induce changes in skeletal muscle similar to those seen in the Bmal1 knockout mouse (Bmal1(-/-) ), a model of advanced ageing. iMSBmal1(-/-) mice develop increased bone calcification and decreased joint collagen, which in combination with the functional changes in skeletal muscle results in altered gait. This study uncovers a fundamental role for the skeletal muscle clock in musculoskeletal homeostasis with potential implications for ageing. ABSTRACT: Disruption of circadian rhythms in humans and rodents has implicated a fundamental role for circadian rhythms in ageing and the development of many chronic diseases including diabetes, cardiovascular disease, depression and cancer. The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop with Bmal1 encoding a core molecular clock transcription factor. Germline Bmal1 knockout (Bmal1 KO) mice have a shortened lifespan, show features of advanced ageing and exhibit significant weakness with decreased maximum specific tension at the whole muscle and single fibre levels. We tested the role of the molecular clock in adult skeletal muscle by generating mice that allow for the inducible skeletal muscle-specific deletion of Bmal1 (iMSBmal1). Here we show that disruption of the molecular clock, specifically in adult skeletal muscle, is associated with a muscle phenotype including reductions in specific tension, increased oxidative fibre type, and increased muscle fibrosis similar to that seen in the Bmal1 KO mouse. Remarkably, the phenotype observed in the iMSBmal1(-/-) mice was not limited to changes in muscle. Similar to the germline Bmal1 KO mice, we observed significant bone and cartilage changes throughout the body suggesting a role for the skeletal muscle molecular clock in both the skeletal muscle niche and the systemic milieu. This emerging area of circadian rhythms and the molecular clock in skeletal muscle holds the potential to provide significant insight into intrinsic mechanisms of the maintenance of muscle quality and function as well as identifying a novel crosstalk between skeletal muscle, cartilage and bone.

Dose-dependency of massage-like compressive loading on recovery of active muscle properties following eccentric exercise: rabbit study with clinical relevance.

BACKGROUND: Optimal strategies for massage and its use in athletes have not been conclusively demonstrated. PURPOSE/STUDY DESIGN: Effects of varying duration, frequency and magnitude of massage-like compressive loading (MLL) on recovery of skeletal muscle active properties (torque angle (T-Θ) relationship) following exercise-induced muscle injury were studied. METHODS: Twenty-four New Zealand White rabbits were surgically instrumented with bilateral peroneal nerve cuffs for stimulation of hindlimb tibialis anterior muscles. Following a bout of eccentric exercise (EEX), rabbits were randomly assigned to a MLL protocol of 0.25 or 0.5 Hz at 5 or 10 N for 15 or 30 min. T-Θ was obtained for 21 tibiotarsal joint angles pre- and post-EEX and post 4 consecutive days of MLL. Muscle wet weight and H&E sections were obtained following final treatments. RESULTS: EEX produced an average 61.8%±2.1 decrease in peak isometric torque output. Differences in torque recovery were found between magnitudes (5 and 10 N; p=0.004, n=12) and frequencies (0.25 and 0.5 Hz; p=0.012, n=12), but no difference for durations (15 and 30 min) with the 0.5 Hz, 10 N, 15 min protocol showing greatest recovery 4 days post-EEX. MLL muscle (n=12) wet weight was 3.22±0.18 g, while no MLL tissue (n=9) weighed 3.74±0.22 g (p=0.029). Histological analysis showed a difference in torn fibres between low-parameter and high-parameter MLL (6.5±1.04 vs 0.5±0.29 per 0.59 mm(2), p=0.005). CONCLUSIONS: Results showed a dose-response effect for magnitude and frequency of MLL on recovery of active muscle properties following EEX. Future studies will investigate underlying biological mechanisms for this enhanced recovery of muscle function.

Short-term repeated human biopsy sampling contributes to changes in muscle morphology and higher outcome variability.

Changes in skeletal muscle are an important aspect of overall health. The collection of human muscle to study cellular and molecular processes for research requires a needle biopsy procedure which, in itself, can induce changes in the tissue. To investigate the effect of repeat tissue sampling, we collected skeletal muscle biopsy samples from vastus lateralis separated by 7 days. Cellular infiltrate, central nucleation, enlarged extracellular matrix, and rounding of muscle fibers were used as indices to define muscle damage, and we found that 16/26 samples (61.5%) revealed at least two of these symptoms in the secondary biopsy. The presence of damage influenced outcome measures usually obtained in human biopsies. Damaged muscle showed an increase in the number of small fibers even though average fiber and fiber type-specific cross-sectional area (CSA) were not different. This included higher numbers of embryonic myosin heavy chain-positive fibers (P = 0.001) as well as elevated satellite cell number (P = 0.02) in the damaged areas and higher variability in satellite cell count in the total area (P = 0.04). Collagen content was higher in damaged (P = 0.0003) as well as nondamaged areas (P = 0.05) of the muscle sections of the damaged compared with the nondamaged group. Myofibrillar protein and ribonucleic acid (RNA) fractional synthesis rates were not significantly different between the damaged compared with the nondamaged group. Results indicate that common outcomes as well as outcome variability in human muscle tissue are affected by previous biopsies. Therefore, the extent of potential damage should be assessed when performing repeated biopsies.NEW & NOTEWORTHY Indices of damage can be found in repeated biopsy samples of nonintervened control legs. Variables, directly and not directly related to muscle damage or regeneration, were compromised in second biopsy. There is a need to determine potential damage within muscle tissue when repeated muscle sampling is part of the study design. Muscle biopsy sampling may be a source of increased heterogeneity in human muscle data.

Extracellular vesicle distribution and localization in skeletal muscle at rest and following disuse atrophy.

BACKGROUND: Skeletal muscle (SkM) is a large, secretory organ that produces and releases myokines that can have autocrine, paracrine, and endocrine effects. Whether extracellular vesicles (EVs) also play a role in the SkM adaptive response and ability to communicate with other tissues is not well understood. The purpose of this study was to investigate EV biogenesis factors, marker expression, and localization across cell types in the skeletal muscle. We also aimed to investigate whether EV concentrations are altered by disuse atrophy. METHODS: To identify the potential markers of SkM-derived EVs, EVs were isolated from rat serum using density gradient ultracentrifugation, followed by fluorescence correlation spectroscopy measurements or qPCR. Single-cell RNA sequencing (scRNA-seq) data from rat SkM were analyzed to assess the EV biogenesis factor expression, and cellular localization of tetraspanins was investigated by immunohistochemistry. Finally, to assess the effects of mechanical unloading on EV expression in vivo, EV concentrations were measured in the serum by nanoparticle tracking analysis in both a rat and human model of disuse. RESULTS: In this study, we show that the widely used markers of SkM-derived EVs, α-sarcoglycan and miR-1, are undetectable in serum EVs. We also found that EV biogenesis factors, including the tetraspanins CD63, CD9, and CD81, are expressed by a variety of cell types in SkM. SkM sections showed very low detection of CD63, CD9, and CD81 in myofibers and instead accumulation within the interstitial space. Furthermore, although there were no differences in serum EV concentrations following hindlimb suspension in rats, serum EV concentrations were elevated in human subjects after bed rest. CONCLUSIONS: Our findings provide insight into the distribution and localization of EVs in SkM and demonstrate the importance of methodological guidelines in SkM EV research.

Transcriptome-wide gene regulation by gentle treadmill walking during the progression of monoiodoacetate-induced arthritis.

OBJECTIVE: Physiotherapies are the most widely recommended conservative treatment for arthritic diseases. The present study was undertaken to examine the molecular mechanisms underlying the effects of gentle treadmill walking (GTW) on various stages of monoiodoacetate-induced arthritis (MIA) to elucidate the basis for the success or failure of such therapies in joint damage. METHODS: Knees were obtained from untreated control rats, rats with MIA that did not undergo GTW, rats with MIA in which GTW regimens were started 1 day post-MIA induction, and rats with MIA in which GTW regimens were started after cartilage damage had progressed to grade 1 or grade 2. The cartilage was examined macroscopically, microscopically, and by microfocal computed tomography imaging. Transcriptome-wide gene expression analysis was performed, and microarray data were assessed by Ingenuity Pathways Analysis to identify molecular functional networks regulated by GTW. RESULTS: GTW intervention started on day 1 post-MIA induction significantly prevented the progression of MIA, but its efficacy was reduced when implemented on knees exhibiting close to grade 1 cartilage damage. GTW accelerated cartilage damage in knees with close to grade 2 damage. Transcriptome-wide gene expression analysis revealed that GTW intervention started 1 day post-MIA inception significantly suppressed inflammation-associated genes and up-regulated matrix-associated gene networks. However, delayed GTW intervention after grade 1 damage had occurred was less effective in suppressing proinflammatory genes or up-regulating matrix synthesis. CONCLUSION: The present findings suggest that GTW suppresses proinflammatory gene networks and up-regulates matrix synthesis to prevent progression of cartilage damage in MIA-affected knees. However, the extent of cartilage damage at the initiation of GTW may be an important determinant of the success or failure of such therapies.

Long-Lasting Impairments in Quadriceps Mitochondrial Health, Muscle Size, and Phenotypic Composition Are Present After Non-invasive Anterior Cruciate Ligament Injury.

INTRODUCTION: Despite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term quadriceps muscle weakness. Derangements in mitochondrial function are a common feature of various atrophying conditions, yet it is unclear to what extent mitochondria are involved in the detrimental sequela of quadriceps dysfunction after ACL injury. Using a preclinical, non-invasive ACL injury rodent model, our objective was to explore the direct effect of an isolated ACL injury on mitochondrial function, muscle atrophy, and muscle phenotypic transitions. METHODS: A total of 40 male and female, Long Evans rats (16-week-old) were exposed to non-invasive ACL injury, while 8 additional rats served as controls. Rats were euthanized at 3, 7, 14, 28, and 56 days after ACL injury, and vastus lateralis muscles were extracted to measure the mitochondrial respiratory control ratio (RCR; state 3 respiration/state 4 respiration), mitochondrial reactive oxygen species (ROS) production, fiber cross sectional area (CSA), and fiber phenotyping. Alterations in mitochondrial function and ROS production were detected using two-way (sex:group) analyses of variance. To determine if mitochondrial characteristics were related to fiber atrophy, individual linear mixed effect models were run by sex. RESULTS: Mitochondria-derived ROS increased from days 7 to 56 after ACL injury (30-100%, P < 0.05), concomitant with a twofold reduction in RCR (P < 0.05). Post-injury, male rats displayed decreases in fiber CSA (days 7, 14, 56; P < 0.05), loss of IIa fibers (day 7; P < 0.05), and an increase in IIb fibers (day 7; P < 0.05), while females displayed no changes in CSA or phenotyping (P > 0.05). Males displayed a positive relationship between state 3 respiration and CSA at days 14 and 56 (P < 0.05), while females only displayed a similar trend at day 14 (P = 0.05). CONCLUSION: Long-lasting impairments in quadriceps mitochondrial health are present after ACL injury and play a key role in the dysregulation of quadriceps muscle size and composition. Our preclinical data indicate that using mitoprotective therapies may be a potential therapeutic strategy to mitigate alterations in muscle size and characteristic after ACL injury.

Mechanotherapy Reprograms Aged Muscle Stromal Cells to Remodel the Extracellular Matrix during Recovery from Disuse.

Aging is accompanied by reduced remodeling of skeletal muscle extracellular matrix (ECM), which is exacerbated during recovery following periods of disuse atrophy. Mechanotherapy has been shown to promote ECM remodeling through immunomodulation in adult muscle recovery, but not during the aged recovery from disuse. In order to determine if mechanotherapy promotes ECM remodeling in aged muscle, we performed single cell RNA sequencing (scRNA-seq) of all mononucleated cells in adult and aged rat gastrocnemius muscle recovering from disuse, with (REM) and without mechanotherapy (RE). We show that fibroadipogenic progenitor cells (FAPs) in aged RE muscle are highly enriched in chemotaxis genes (Csf1), but absent in ECM remodeling genes compared to adult RE muscle (Col1a1). Receptor-ligand (RL) network analysis of all mononucleated cell populations in aged RE muscle identified chemotaxis-enriched gene expression in numerous stromal cell populations (FAPs, endothelial cells, pericytes), despite reduced enrichment of genes related to phagocytic activity in myeloid cell populations (macrophages, monocytes, antigen presenting cells). Following mechanotherapy, aged REM mononuclear cell gene expression resembled adult RE muscle as evidenced by RL network analyses and KEGG pathway activity scoring. To validate our transcriptional findings, ECM turnover was measured in an independent cohort of animals using in vivo isotope tracing of intramuscular collagen and histological scoring of the ECM, which confirmed mechanotherapy-mediated ECM remodeling in aged RE muscle. Our results highlight age-related cellular mechanisms underpinning the impairment to complete recovery from disuse, and also promote mechanotherapy as an intervention to enhance ECM turnover in aged muscle recovering from disuse.

Temporal disruption of neuromuscular communication and muscle atrophy following noninvasive ACL injury in rats.

Many patients with anterior cruciate ligament (ACL) injuries have persistent quadriceps muscle atrophy, even after considerable time in rehabilitation. Understanding the factors that regulate muscle mass, and the time course of atrophic events, is important for identifying therapeutic interventions. With a noninvasive animal model of ACL injury, a longitudinal study was performed to elucidate key parameters underlying quadriceps muscle atrophy. Male Long-Evans rats were euthanized at 6, 12, 24, or 48 h or 1, 2, or 4 wk after ACL injury that was induced via tibial compression overload; controls were not injured. Vastus lateralis muscle size was determined by wet weight and fiber cross-sectional area (CSA). Evidence of disrupted neuromuscular communication was assessed via the expression of neural cell adhesion molecule (NCAM) and genes associated with denervation and neuromuscular junction instability. Abundance of muscle RING-finger protein-1 (MuRF-1), muscle atrophy F-box (MAFbx), and 45 s pre-rRNA along with 20S proteasome activity were determined to investigate mechanisms related to muscle atrophy. Finally, muscle damage-related parameters were assessed by measuring IgG permeability, centronucleation, CD68 mRNA, and satellite cell abundance. When compared with controls, we observed a greater percentage of NCAM-positive fibers at 6 h postinjury, followed by higher MAFbx abundance 48 h postinjury, and higher 20S proteasome activity at 1 wk postinjury. A loss of muscle wet weight, smaller fiber CSA, and the elevated expression of run-related transcription factor 1 (Runx1) were also observed at the 1 wk postinjury timepoint relative to controls. There also were no differences observed in any damage markers. These results indicate that alterations in neuromuscular communication precede the upregulation of atrophic factors that regulate quadriceps muscle mass early after noninvasive ACL injury.NEW & NOTEWORTHY A novel preclinical model of ACL injury was used to establish that acute disruptions in neuromuscular communication precede atrophic events. These data help to establish the time course of muscle atrophy after ACL injury, suggesting that clinical care may benefit from the application of acute neurogenic interventions and early gait reloading strategies.

Age-Related Susceptibility to Muscle Damage Following Mechanotherapy in Rats Recovering From Disuse Atrophy.

The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14 days of hindlimb suspension, followed by 7 days of recovery with (RE + M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross-sectional area were observed between RE and RE + M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin-/laminin+ fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.

Cellular and Molecular Mechanisms of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

SUMMARY: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emerging and highly treatable cancer of the immune system that can form around textured-surface breast implants. Although the underlying cause has yet to be elucidated, an emerging theme-linking pathogenesis to a chronic inflammatory state-continues to dominate the current literature. Specifically, the combination of increasing mutation burden and chronic inflammation leads to aberrant T-cell clonal expansion. However, the impetus remains largely unknown. Proposed mechanisms include a lipopolysaccharide endotoxin response, oncogenic transformation related to viral infection, associated trauma to the breast pocket, particulate matter digestion by capsular macrophages, chronic allergic inflammation, and genetic susceptibility. The Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway is a major signaling pathway that regulates a variety of intracellular growth and survival processes. Constitutive activation of JAK-STAT3 has been implicated in several malignancies, including lymphomas, and has recently been identified as a potential key mediator in BIA-ALCL. The purpose of this article is to review the cellular and molecular mechanisms of BIA-ALCL with a focus on the role of oncogenic JAK-STAT3 signaling in BIA-ALCL tumorigenesis and progression. Selected experimental work from the authors' group on aberrant JAK-STAT3 signaling in BIA-ALCL is also included. The authors discuss how an inflammatory microenvironment may facilitate malignant transformation through the JAK-STAT3 pathway-highlighting its potential mechanistic role. The authors' hope is that further investigation of this signaling pathway will reveal avenues for using JAK-STAT3 signaling as a prognostic indicator and novel therapeutic target in the case of advanced disease.