Early Neuromuscular Electrical Stimulation Preserves Muscle Size and Quality and Maintains Systemic Levels of Signaling Mediators of Muscle Growth and Inflammation in Patients with Traumatic Brain Injury: A Randomized Clinical Trial.

Objective: To investigate the effects of an early neuromuscular electrical stimulation (NMES) protocol on muscle quality and size as well as signaling mediators of muscle growth and systemic inflammation in patients with traumatic brain injury (TBI). Design: Two-arm, single-blinded, parallel-group, randomized, controlled trial with a blinded assessment. Setting. Trauma intensive care unit at a university hospital. Participants. Forty consecutive patients on mechanical ventilation (MV) secondary to TBI were prospectively recruited within the first 24 hours following admission. Interventions. The intervention group (NMES; n = 20) received a daily session of NMES on the rectus femoris muscle for five consecutive days (55 min/each session). The control group (n = 20) received usual care. Main Outcome Measures. Muscle echogenicity and thickness were evaluated by ultrasonography. A daily blood sample was collected to assess circulating levels of insulin-like growth factor I (IGF-I), inflammatory cytokines, and matrix metalloproteinases (MMP). Results: Both groups were similar at baseline. A smaller change in muscle echogenicity and thickness (difference between Day 1 and Day 7) was found in the control group compared to the NMES group (29.9 ± 2.1 vs. 3.0 ± 1.2, p < 0.001; -0.79 ± 0.12 vs. -0.01 ± 0.06, p < 0.001, respectively). Circulating levels of IGF-I, pro-inflammatory cytokines (IFN-y), and MMP were similar between groups. Conclusion: An early NMES protocol can preserve muscle size and quality and maintain systemic levels of signaling mediators of muscle growth and inflammation in patients with TBI. This trial is registered with https://www.ensaiosclinicos.gov.br under number RBR-2db.

The Influence of Hip and Knee Joint Angles on Quadriceps Muscle-Tendon Unit Properties during Maximal Voluntary Isometric Contraction.

Determining how the quadriceps femoris musculotendinous unit functions, according to hip and knee joint angles, may help with clinical decisions when prescribing knee extension exercises. We aimed to determine the effect of hip and knee joint angles on structure and neuromuscular functioning of all constituents of the quadriceps femoris and patellar tendon properties. Twenty young males were evaluated in four positions: seated and supine in both 20° and 60° of knee flexion (SIT20, SIT60, SUP20, and SUP60). Peak knee extension torque was determined during maximal voluntary isometric contraction (MVIC). Ultrasound imaging was used at rest and during MVIC to characterize quadriceps femoris muscle and tendon aponeurosis complex stiffness. We found that peak torque and neuromuscular efficiency were higher for SUP60 and SIT60 compared to SUP20 and SIT20 position. We found higher fascicle length and lower pennation angle in positions with the knee flexed at 60°. The tendon aponeurosis complex stiffness, tendon force, stiffness, stress, and Young's modulus seemed greater in more elongated positions (60°) than in shortened positions (20°). In conclusion, clinicians should consider positioning at 60° of knee flexion rather than 20°, regardless if seated or supine, during rehabilitation to load the musculotendinous unit enough to stimulate a cellular response.

Neuromuscular disorders in women and men with spinal cord injury are associated with changes in muscle and tendon architecture.

OBJECTIVE: The present study aimed to determine the association between neuromuscular function, motor function impairment, and muscle and tendon structures in individuals with spinal cord injury (SCI) compared to a control (non-disabled) population. DESIGN: A cross-sectional study with a control group. SETTING: Center of Adapted Sports Training and Special Physical Education. PARTICIPANTS: Fifteen individuals with SCI and motor function impairments participated in the study. A paired non-disabled group was recruited for comparison. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Muscle (biceps brachii, rectus femoris, vastus lateralis, vastus medialis, and tibialis anterior) and tendon (quadriceps and patellar tendons) structures were assessed by ultrasound imaging (thickness, pennation angle, fascicle length, and echogenicity). Neuromuscular electrophysiological disorders were also assessed using electrodiagnosis techniques (stimulus non-responsivity and chronaxie) in the same muscles. RESULTS: Except for the biceps brachii muscle, muscle thickness, pennation angle, and fascicle length were lower (p < 0.01) while echogenicity and chronaxie were greater (p < 0.01) in SCI participants. The SCI participants had a higher prevalence of neuromuscular electrophysiological disorders for all muscles, except the biceps brachii. CONCLUSION: Neuromuscular disorders occur in association with muscle and tendon maladaptation in individuals with chronic SCI. A higher prevalence of electrophysiological disorders suggests an acquired polyneuromyopathy for muscles with motor function impairment even though the muscle was innerved, in addition to widespread muscle atrophy.

Moderate Treadmill Training Induces Limited Effects on Quadriceps Muscle Hypertrophy in Mice Exposed to Cigarette Smoke Involving Metalloproteinase 2.

BACKGROUND: Long-term cigarette smoke (CS) induces substantive extrapulmonary effects, including musculoskeletal system disorders. Exercise training seems to protect long-term smokers against fiber atrophy in the locomotor muscles. Nevertheless, the extracellular matrix (ECM) changes in response to aerobic training remain largely unknown. Thus, we investigated the effects of moderate treadmill training on aerobic performance, cross-sectional area (CSA), fiber distribution, and metalloproteinase 2 (MMP-2) activity on quadriceps muscle in mice exposed to chronic CS. METHODS: Male mice were randomized into four groups: control or smoke (6 per group) and exercise or exercise+smoke (5 per group). Animals were exposed to 12 commercially filtered cigarettes per day (0.8 mg of nicotine, 10 mg of tar, and 10 mg of CO per cigarette). The CSA, fibers distribution, and MMP-2 activity by zymography were assessed after a period of treadmill training (50% of maximal exercise capacity for 60 min/day, 5 days/week) for 24 weeks. RESULTS: The CS exposure did not change CSA compared to the control group (p>0.05), but minor fibers in the frequency distribution (<1000 µm2) were observed. Long-term CS exposure attenuated CSA increases in exercise conditions (smoke+exercise vs exercise) while did not impair aerobic performance. Quadriceps CSA increased in mice nonsmoker submitted to aerobic training (p = 0.001). There was higher pro-MMP-2 activity in the smoke+exercise group when compared to the smoke group (p = 0.01). Regarding active MMP-2, the exercise showed higher values when compared to the control group (p = 0.001). CONCLUSION: Moderate treadmill training for 24 weeks in mice exposed to CS did not modify CSA, despite inducing higher pro-MMP-2 activity in the quadriceps muscle, suggesting limited effects on ECM remodeling. Our findings may contribute to new insights into molecular mechanisms for CS conditions.

High-protein diet associated with resistance training reduces cardiac TNF-α levels and up-regulates MMP-2 activity in rats.

The consumption of high-protein diets (HPD) is associated with resistance training (RT) due to effects on metabolism. However, little is known about these effects on cardiac tissue. This study aimed to investigate effects of HPD and RT on cardiac biomarkers. 18 rats were divided into normo-protein (NPD), and HPD groups: NPD-Control, NPD-RT, HPD-Control, and HPD-RT. Interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-a), nitric oxide (NO), activity of metalloproteinase-2 (MMP-2), and vascular factor (VEGF) were analysed. RT was effective in regulating body weight, increasing strength, and reducing food consumption (p < .05). HPD induces higher levels of interleukin 6 (p = .0169), and lowers NO (p < .0001). When associated with RT, the HPD decreases levels of tumour necrosis factor alpha, while enhances NO, and MMP activity (p < .05). The association of RT with HDP decreases inflammatory parameters and indicates an enhancement in the molecular parameters of cardiac tissue.

Intra- and inter-rater reliability for the measurement of the cross-sectional area of ankle tendons assessed by magnetic resonance imaging.

BACKGROUND: The cross-sectional area (CSA) records make an essential measurement for determining the mechanical properties of tendons, such as stress and strength. However, there is no consensus regarding the best method to record the CSA from different tendons. PURPOSE: To determine intra- and inter-rater reliability for CSA measures from magnetic resonance imaging (MRI) of the following tendons: tibialis anterior; tibialis posterior; fibularis longus and brevis; and Achilles. MATERIAL AND METHODS: We designed an observational study with repeated measures taken from a convenience sample of 20 participants diagnosed with acute or chronic ankle sprain. Two independent raters took three separate records from the CSA of ankle tendon images of each MRI slice. The intra-class correlation coefficient (ICC) and 95% limits of agreement (LoA) defined the quality (associations) and magnitude (differences), respectively, of intra- and inter-rater reliability on the measures plotted by the Bland-Altman method. RESULTS: Data showed very high intra- and inter-rater correlations for measures taken from all tendons analyzed (ICC 0.952-0.999). It also revealed an excellent agreement between raters (0.12%-2.3%), with bias no higher than 2 mm2 and LoA in the range of 4.4-7.9 mm2. The differences between repeated measures recorded from the thinnest tendons (fibularis longus and brevis) revealed the lowest bias and narrowest 95% LoA. CONCLUSION: Reliability for the CSA of ankle tendons measured from MRI taken by independent rates was very high, with the smallest differences between raters observed when the thinnest tendon was analyzed.

Acute lateral ankle sprain alters muscle and tendon properties: Case series.

BACKGROUND: Acute lateral ankle sprain (LAS) is the most prevalent acute sports trauma. Ankle muscle atrophy and tendon volume decrease have not been analyzed concomitantly with functional impairment and pain following LAS. The objective of the present study was to investigate muscle cross-section area (CSA), tendon CSA and volume, ankle function, and pain in individuals who suffered an acute LAS. METHODS: A series of cases, cross-sectional study with 20 participants who suffered moderate (grade II) and severe (grade III) acute LAS was undertaken. CSA for muscles (Tibialis Posterior, Fibularis, and Soleus) and tendons (Tibialis Anterior, Tibialis posterior, Fibularis, and Achilles), and volume were measured by magnetic resonance imaging (MRI) less than 48 h (baseline) and 6-weeks after the acute LAS. Ankle function (Cumberland Ankle Instability Tool [CAIT] and Foot and Ankle Outcome Score [FAOS]), ankle mechanical instability (Anterior Drawer Test [ADT]), and pain were also assessed. RESULTS: All tendons and muscles showed a significant reduction in CSA and volume between baseline and 6-weeks (P < .001). A significant decrease in ankle function was observed 6 weeks after the LAS, along with a reduction in pain and mechanical instability (P = .001). Regarding sprain magnitude, the only difference observed was greater atrophy in muscle CSA in participants with grade III ankle sprain. CONCLUSION: Patients with acute LAS showed atrophy of ankle muscles and decreased tendon volume and CSA, followed by function impairments at 6-week follow-up. LEVEL OF EVIDENCE: IV, Case series study.

Time course of 3D fibrocartilage formation by expanded human meniscus fibrochondrocytes in hypoxia.

Adult human meniscus fibrocartilage is avascular and nonhealing after injury. Meniscus tissue engineering aims to replace injured meniscus with lab-grown fibrocartilage. Dynamic culture systems may be necessary to generate fibrocartilage of sufficient mechanical properties for implantation; however, the optimal static preculture conditions before initiation of dynamic culture are unknown. This study thus investigated the time course of fibrocartilage formation by human meniscus fibrochondrocytes on a three-dimensional biomaterial scaffold under various static conditions. Human meniscus fibrochondrocytes from partial meniscectomy were expanded to passage 1 (P1) or P2 (3.0 ± 0.4 and 6.5 ± 0.6 population doublings), seeded onto type I collagen scaffolds, and grown in hypoxia (HYP, 3% O2 ) or normoxia (NRX, 20% O2 ) for 3, 6, and 9 weeks. Mechanical properties were not different between P1 and P2 cell-based constructs. Mechanical properties were lower in HYP, increased continually in NRX only, and were positively correlated with glycosaminoglycan content and accumulation of hyaline cartilage-like matrix components. The most mechanically competent tissues (NRX/9 weeks) reached 1/5 of the native meniscus instantaneous compression modulus but had an increasingly hypertrophic matrix-forming phenotype. HYP consistently suppressed the hypertrophic phenotype. The results provide baselines of engineered meniscus fibrocartilage properties under static conditions, which can be used to select a preculture strategy for dynamic culture depending on the desired combination of mechanical properties, hyaline cartilage-like matrix abundance, and hypertrophic phenotype.

Paternal Resistance Exercise Modulates Skeletal Muscle Remodeling Pathways in Fathers and Male Offspring Submitted to a High-Fat Diet.

Although some studies have shown that a high-fat diet (HFD) adversely affects muscle extracellular matrix remodeling, the mechanisms involved in muscle trophism, inflammation, and adipogenesis have not been fully investigated. Thus, we investigated the effects of 8 weeks of paternal resistance training (RT) on gene and protein expression/activity of critical factors involved in muscle inflammation and remodeling of fathers and offspring (offspring exposed to standard chow or HFD). Animals were randomly distributed to constitute sedentary fathers (SF; n = 7; did not perform RT) or trained fathers (TF n = 7; performed RT), with offspring from mating with sedentary females. After birth, 28 male pups were divided into four groups (n = 7 per group): offspring from sedentary father submitted either to control diet (SFO-C) or high-fat diet (SFO-HF) and offspring from trained father submitted to control diet (TFO-C) or high-fat diet (TFO-HF). Our results show that an HFD downregulated collagen mRNA levels and upregulated inflammatory and atrophy pathways and adipogenic transcription factor mRNA levels in offspring gastrocnemius muscle. In contrast, paternal RT increased MMP-2 activity and decreased IL-6 levels in offspring exposed to a control diet. Paternal RT upregulated P70s6k and Ppara mRNA levels and downregulated Atrogin1 mRNA levels, while decreasing NFκ-B, IL-1ß, and IL-8 protein levels in offspring exposed to an HFD. Paternal physical training influences key skeletal muscle remodeling pathways and inflammatory profiles relevant for muscle homeostasis maintenance in offspring submitted to different diets.

The Effect of Quadriceps Muscle Length on Maximum Neuromuscular Electrical Stimulation Evoked Contraction, Muscle Architecture, and Tendon-Aponeurosis Stiffness.

Muscle-tendon unit length plays a crucial role in quadriceps femoris muscle (QF) physiological adaptation, but the influence of hip and knee angles during QF neuromuscular electrical stimulation (NMES) is poorly investigated. We investigated the effect of muscle length on maximum electrically induced contraction (MEIC) and current efficiency. We secondarily assessed the architecture of all QF constituents and their tendon-aponeurosis complex (TAC) displacement to calculate a stiffness index. This study was a randomized, repeated measure, blinded design with a sample of twenty healthy men aged 24.0 ± 4.6. The MEIC was assessed in four different positions: supine with knee flexion of 60° (SUP60); seated with knee flexion of 60° (SIT60); supine with knee flexion of 20° (SUP20), and seated with knee flexion of 20° (SIT20). The current efficiency (MEIC/maximum tolerated current amplitude) was calculated. Ultrasonography of the QF was performed at rest and during NMES to measure pennation angle (θ p ) and fascicle length (L f ), and the TAC stiffness index. MEIC and current efficiency were greater for SUP60 and SIT60 compared to SUP20 and SIT20. The vastus lateralis and medialis showed lower θ p and higher L f at SUP60 and SIT60, while for the rectus femoris, in SUP60 there were lower θ p and higher L f than in all positions. The vastus intermedius had a similar pattern to the other vastii, except for lack of difference in θ p between SIT60 compared to SUP20 and SIT20. The TAC stiffness index was greater for SUP60. We concluded that NMES generate greater torque and current efficiency at 60° of knee flexion, compared to 20°. For these knee angles, lengthening the QF at the hip did not promote significant change. Each QF constituent demonstrated muscle physiology patterns according to hip and/or knee angles, even though a greater L f and lower θ p were predominant in SUP60 and SIT60. QF TAC index stiffened in more elongated positions, which probably contributed to enhanced force transmission and slightly higher torque in SUP60. Our findings may help exercise physiologist better understand the impact of hip and knee angles on designing more rational NMES stimulation strategies. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT03822221.

Human engineered meniscus transcriptome after short-term combined hypoxia and dynamic compression.

This study investigates the transcriptome response of meniscus fibrochondrocytes (MFCs) to the low oxygen and mechanical loading signals experienced in the knee joint using a model system. We hypothesized that short term exposure to the combined treatment would promote a matrix-forming phenotype supportive of inner meniscus tissue formation. Human MFCs on a collagen scaffold were stimulated to form fibrocartilage over 6 weeks under normoxic (NRX, 20% O2) conditions with supplemented TGF-ß3. Tissues experienced a delayed 24h hypoxia treatment (HYP, 3% O2) and then 5 min of dynamic compression (DC) between 30 and 40% strain. Delayed HYP induced an anabolic and anti-catabolic expression profile for hyaline cartilage matrix markers, while DC induced an inflammatory matrix remodeling response along with upregulation of both SOX9 and COL1A1. There were 41 genes regulated by both HYP and DC. Overall, the combined treatment supported a unique gene expression profile favouring the hyaline cartilage aspect of inner meniscus matrix and matrix remodeling.

Resistance Training Modulates the Matrix Metalloproteinase-2 Activity in Different Trabecular Bones in Aged Rats.

BACKGROUND: Aging decreases osteogenic ability, inducing harmful effects on the bone extracellular matrix (ECM), while exercise training has been indicated as a tool to counteract bone disorders related to advancing age. The modulation of bone ECM is regulated by several types of matrix metalloproteinase (MMP); however, MMP-2 activity in different trabecular bones in response to resistance training (RT) has been neglected. Remodeling differs in different bones under the application of the same mechanical loading. Thus, we investigated the effects of 12 weeks of RT on MMP-2 activity in the lumbar vertebra (L6), tibia, and femur of young (3 months) and older rats (21 months). METHODS: Twenty Wistar rats were divided into four groups (five animals per group): young sedentary or trained and older sedentary or trained. The 12-week RT consisted of climbing a 1.1-m vertical ladder three times per week with progressive weights secured to the animals' tails. The animals were killed 48 h after the end of the experimental period. The MMP-2 activity was assessed by the zymography method. RESULTS: The aging process induced lower MMP-2 activity in the lumbar vertebrae and tibia (p=0.01). RT upregulated pro, intermediate, and active MMP-2 activity in the tibia of young rats (p=0.001). RT also upregulated pro and active MMP-2 activity in the lumbar vertebrae and tibia with advancing age (p=0.01). There was no significant difference (p>0.05) between groups for MMP-2 of the femur, regardless of age and RT. CONCLUSION: The aging process impairs MMP-2 activity, but RT is a potential therapeutic approach to minimize the deleterious effects of ECM degeneration in different aged bones. Distinct MMP-2 responses to exercise training may result in specific remodeling processes.

Resistance training decreases matrix metalloproteinase-2 activity in quadriceps tendon in a rat model of osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a degenerative disease that induces peri-articular tissue degradation. OA induces an imbalance between synthesis and degradation of the extracellular matrix components in favor of catabolic events, promoting pathological remodeling and involving degradative enzymes, such as matrix metalloproteinases (MMPs). OBJECTIVE: This study aimed to investigate the effects of 8-weeks resistance training (RT) on MMP-2 activity in the quadriceps tendon and patellar tendon in an OA model. METHODS: Twenty-four Wistar rats were randomly divided into six groups: Control, Exercise, Sham, Sham with Exercise, OA, and OA with Exercise (OAE). The OA model was performed by anterior cruciate ligament transection surgery on the left knee. The 8-week RT consisted of climbing a 1.1-m vertical ladder three times per week with progressive weights secured to the animals' tails. MMP-2 activity was analyzed by zymography. RESULTS: The OAE group displayed lower pro, intermediate, and active MMP-2 activity in the quadriceps tendon compared with the OA group (p<0.05). For the patellar tendon, there was no significant difference between the OAE group compared with the other groups (p>0.05) for pro, intermediate, and active MMP-2 activity. Moreover, MMP-2 activity differed between tissues, the OA and OAE groups presented lower pro, intermediate, and active MMP-2 activity in the quadriceps tendon compared to the patellar tendon. CONCLUSION: RT induced down-regulated MMP-2 activity in the quadriceps tendon. RT is a potential therapeutic approach to minimize the deleterious effects of extracellular matrix degeneration.

Paternal Resistance Training Modulates Calcaneal Tendon Proteome in the Offspring Exposed to High-Fat Diet.

The increase in high-energy dietary intakes is a well-known risk factor for many diseases, and can also negatively impact the tendon. Ancestral lifestyle can mitigate the metabolic harmful effects of offspring exposed to high-fat diet (HF). However, the influence of paternal exercise on molecular pathways associated to offspring tendon remodeling remains to be determined. We investigated the effects of 8 weeks of paternal resistance training (RT) on offspring tendon proteome exposed to standard diet or HF diet. Wistar rats were randomly divided into two groups: sedentary fathers and trained fathers (8 weeks, three times per week, with 8-12 dynamic movements per climb in a stair climbing apparatus). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups (five animals per group): offspring from sedentary fathers were exposed either to control diet (SFO-C), or to high-fat diet (SFO-HF); offspring from trained fathers were exposed to control diet (TFO-C) or to a high-fat diet (TFO-HF). The Nano-LC-MS/MS analysis revealed 383 regulated proteins among offspring groups. HF diet induced a decrease of abundance in tendon proteins related to extracellular matrix organization, transport, immune response and translation. On the other hand, the changes in the offspring tendon proteome in response to paternal RT were more pronounced when the offspring were exposed to HF diet, resulting in positive regulation of proteins essential for the maintenance of tendon integrity. Most of the modulated proteins are associated to biological pathways related to tendon protection and damage recovery, such as extracellular matrix organization and transport. The present study demonstrated that the father's lifestyle could be crucial for tendon homeostasis in the first generation. Our results provide important insights into the molecular mechanisms involved in paternal intergenerational effects and potential protective outcomes of paternal RT.

Microcurrent and adipose-derived stem cells modulate genes expression involved in the structural recovery of transected tendon of rats.

Tendon injuries are common and have a high incidence of re-rupture that can cause loss of functionality. Therapies with adipose-derived stem cells (ASC) and the microcurrent (low-intensity electrical stimulation) application present promising effects on the tissue repair. We analyzed the expression of genes and the participation of some molecules potentially involved in the structural recovery of the Achilles tendon of rats, in response to the application of both therapies, isolated and combined. The tendons were distributed in five groups: normal (N), transected (T), transected and ASC (C) or microcurrent (M) or with ASC, and microcurrent (MC). Microcurrent therapy was beneficial for tendon repair, as it was observed a statistically significant increase in the organization of the collagen fibers, with involvement of the TNC, CTGF, FN, FMDO, and COL3A1 genes as well as PCNA, IL-10, and TNF-α. ASC therapy significantly increased the TNC and FMDO genes expression with no changes in the molecular organization of collagen. With the association of therapies, a significant greater collagen fibers organization was observed with involvement of the FMOD gene. The therapies did not affect the expression of COL1A1, SMAD2, SMAD3, MKX, and EGR1 genes, nor did they influence the amount of collagen I and III, caspase-3, tenomodulin (Tnmd), and hydroxyproline. In conclusion, the application of the microcurrent isolated or associated with ASC increased the organization of the collagen fibers, which can result in a greater biomechanical resistance in relation to the tendons treated only with ASC. Future studies will be needed to demonstrate the biological effects of these therapies on the functional recovery of injured tendons.

Remodeling process in bone of aged rats in response to resistance training.

AIMS: We investigate the effects of RT on the mechanical function, gene, and protein expression of key factors involved in bone remodeling during aging. MAIN METHODS: Male rats of 3 and 21 months of age were randomly allocated into four groups (8 per group): young sedentary (YS), young trained (YT), old sedentary (OS), and old trained (OT). RT was performed three times per week (12 weeks). Bone tenacity and stiffness were measured by biomechanical tests and mRNA levels of COL1A1, MEPE, SOST, OPG, BMP-2, PPAR-y, MMP-2-9-13, and TIMP-1 were evaluated by quantitative PCR. COL1A1 protein and MMP-2 activity were detected by western blotting and zymography assays. KEY FINDINGS: Aging increased stiffness, while BMP-2, OPG, COL1A1 and MMP-2 mRNA levels reduced (OS vs YS; p ≤ 0.05). RT increased the tenacity of the femur and reduced PPAR-γ regardless of age (YT vs. YS; OT vs. OS; p ≤ 0.05). RT downregulated SOST mRNA levels only in the OT group (vs. OS group, p ≤ 0.05). RT mitigated the age-associated increase in MMP-9 mRNA levels (p ≤ 0.05). In young animals, upregulation in MEPE, MMP-13, TIMP-1 were observed after RT, as well an increase in COL1A1 protein and MMP-2 activity (p ≤ 0.05). SIGNIFICANCE: RT improved bone tenacity independent of aging, which is relevant for mechanical function, while, at protein levels, RT upregulated MMP-2 activity and collagen 1 only in young rats. This study highlights the importance of exercise on bone health and identifies specific molecular changes in response to RT. Our findings provide insights into the mechanisms involved in age-related changes.

Proteomic changes in skeletal muscle of aged rats in response to resistance training.

Sarcopenia is a multifactorial process defined by loss of strength and skeletal muscle mass, which leads to a reduction in muscle cross-sectional area (CSA). Although resistance training (RT) has been indicated as a tool to counteract sarcopenia, the protein profile associated with skeletal muscle adaptations remains to be determined. We investigated the effects of 12 weeks of RT on the skeletal muscle proteome profile and CSA of young and older rats. Twenty-four animals were divided into four groups: young sedentary or trained and older sedentary or trained (six animals per group). A 12-week RT protocol was performed, which consisted of climbing a vertical ladder. The proteins from the gastrocnemius were analysed by LC-ESI-MS/MS. One-hundred and thirty-one proteins were identified, of which 28 were assessed between the groups. Ageing induced an increase in proteins associated with the glycolytic pathway, transport and stress response, which represent crucial mechanisms for muscle adaptation. RT upregulated metabolic enzymes, anti-oxidant activity and transport proteins, besides increasing hypertrophy, regardless of age, suggesting a beneficial adaptation to mitigate age-related sarcopenia. RT reduced muscle atrophy through the regulation of stress response and by increasing proteins related to energy production and transport, which in turn might protect tissue damage arising from exercise and ageing. SIGNIFICANCE OF THE STUDY: Protein abundance levels related to the metabolic process and stress response were increased in the aged muscle. RT proved to be an important intervention capable of inducing significant effects on muscle proteome regardless of ageing, due to upregulation of glycolytic enzymes, and anti-oxidant and transport proteins. This effect could lead to a beneficial adaptation in muscle structure, cellular function and overall homeostasis maintenance. This study contributes to better understanding of the basic biology of ageing and clarifies more profoundly the molecular networks behind physiological adaptations promoted by exercise training. Therefore, the results open new perspectives and insights for studies based on transcriptomics, metabolomics and functional assays.

Identificação de fatores de risco para quedas em indivíduos com esclerose múltipla: uma revisão sistemática de estudos prospectivos / Identificación de los factores de riesgo de caídas en individuos con esclerosis múltiple: una revisión sistemática de estudios prospectivos / Identification of risk factors for falls in people with multiple sclerosis: a systematic review of prospective studies

RESUMO O objetivo deste estudo foi identificar, a partir de uma revisão sistemática, variáveis clínicas, instrumentais e demográficas associadas com maior risco de queda em indivíduos com esclerose múltipla (EM), com base em dados prospectivos. A pesquisa foi conduzida nas bases de dados Medline, Web of Science, Bireme e CINAHL, utilizando os descritores "esclerose múltipla", "quedas", "quedas acidentais", "risco de quedas", "controle postural" e "equilíbrio", seguido de buscas manuais. Foram considerados elegíveis estudos de coorte prospectivos, com período mínimo de acompanhamento das quedas de três meses, que avaliassem a associação de determinada variável demográfica, clínica ou instrumental em relação a maior risco de queda em indivíduos com EM. A escala de Newcastle-Ottawa modificada foi utilizada para avaliação da qualidade metodológica dos estudos incluídos. Foram identificados 357 estudos, 12 dos quais foram incluídos na revisão sistemática, com total de 1.270 pacientes incluídos. Destes, 740 (58,26%) pacientes apresentaram um ou mais episódios de queda, 396 (31,18%) apresentaram episódios de queda recorrentes (2≥quedas no período estipulado), e 530 (41,74%) não apresentaram nenhum episódio. Com exceção da espasticidade e do impacto da dupla tarefa na velocidade da marcha, todas as variáveis investigadas apresentaram resultados conflitantes quanto às suas associações a maior risco de quedas. São necessários mais estudos que apresentem homogeneidade dos fenótipos clínicos de indivíduos com EM, além da utilização de instrumentos de avaliação validados, a fim de estabelecer uma associação robusta de outras variáveis clínicas, instrumentais e demográficas com maior risco de queda.

RESUMEN El objetivo de este estudio fue identificar, a partir de una revisión sistemática, variables clínicas, instrumentales y demográficas asociadas con un mayor riesgo de caída en individuos con esclerosis múltiple (EM), con base en datos prospectivos. La búsqueda se realizó en las bases de datos: Medline, Web of Science, Bireme y CINAHL, utilizando los descriptores "esclerosis múltiple", "caídas", "caídas accidentales", "riesgo de caídas", "control postural" y "equilibrio", seguido de búsquedas manuales. Se consideraron elegibles los estudios de cohorte prospectivos con un período de seguimiento mínimo de caídas de tres meses, que evaluaron la asociación de una variable demográfica, clínica o instrumental en relación con el mayor riesgo de caídas en individuos con EM. La escala modificada de Newcastle-Ottawa se utilizó para evaluar la calidad metodológica de los estudios incluidos. Se identificaron 357 estudios, 12 de los cuales se incluyeron en la revisión sistemática, con un total de 1.270 pacientes incluidos. De estos, 740 (58,26%) pacientes tuvieron uno o más episodios de caída, 396 (31,18%) presentaron episodios de caída recurrentes (2≥caídas en el período estipulado), y 530 (41,74%) no presentaron ningún episodio. Con excepción de la espasticidad y del impacto de la doble tarea en la velocidad de la marcha, todas las variables investigadas presentaron resultados conflictivos en cuanto a sus asociaciones a mayor riesgo de caídas. Se requieren más estudios que presenten homogeneidad de los fenotipos clínicos de pacientes con EM, además del uso de instrumentos de evaluación validados, para establecer una asociación robusta de otras variables clínicas, instrumentales y demográficas con mayor riesgo de caída.

ABSTRACT The objective of this study was to identify demographic, clinical, and instrumental variables associated with falls in people with multiple sclerosis (MS), via systematic review, based on prospective data. The search was conducted in these databases: Medline, Web of Science, Bireme e CINAHL via a search strategy that combined the descriptors "multiple sclerosis", "falls", "accidental falls", "fall risk", "postural control" and "balance", followed by manual search. Eligibility criteria were prospective cohort studies with a minimum 3-month follow-up of falls that assessed the association of a demographic, clinical or instrumental variable in relation to a higher fall risk in people with MS. The modified Newcastle-Ottawa Quality Assessment Scale was used for study quality assessment. A total of 357 studies were identified, of which 12 were included in the systematic review and 1,270 patients were included. In this study, 740 (58.26%) patients were classified as fallers, 396 (31.18%) patients had recurrent falls (2≥falls within the stipulated period) and 530 patients (41.74%) were classified as non-fallers. Except for spasticity and dual task cost in gait speed, all investigated variables showed conflicting results regarding their association with a higher fall risk. More studies with clinical homogeneity phenotypes of MS individuals and using validated assessment instruments are necessary to establish a robust association of other clinical, instrumental, and demographic variables with a higher fall risk.

Calcaneal Tendon Plasticity Following Gastrocnemius Muscle Injury in Rat.

Cross-talk between skeletal muscle and tendon is important for tissue homeostasis. Whereas the skeletal muscle response to tendon injury has been well-studied, to the best of our knowledge the tendon response to skeletal muscle injury has been neglected. Thus, we investigated calcaneal tendon extracellular matrix (ECM) remodeling after gastrocnemius muscle injury using a rat model. Wistar rats were randomly divided into four groups: control group (C; animals that were not exposed to muscle injury) and harvested at different time points post gastrocnemius muscle injury (3, 14, and 28 days) for gene expression, morphological, and biomechanical analyses. At 3 days post injury, we observed mRNA-level dysregulation of signaling pathways associated with collagen I accompanied with disrupted biomechanical properties. At 14 days post injury, we found reduced collagen content histologically accompanied by invasion of blood vessels into the tendon proper and an abundance of peritendinous sheath cells. Finally, at 28 days post injury, there were signs of recovery at the gene expression level including upregulation of transcription factors related to ECM synthesis, remodeling, and repair. At this time point, tendons also presented with increased peritendinous sheath cells, decreased adipose cells, higher Young's modulus, and lower strain to failure compared to the uninjured controls and all post injury time points. In summary, we demonstrate that the calcaneal tendon undergoes extensive ECM remodeling in response to gastrocnemius muscle injury leading to altered functional properties in a rat model. Tendon plasticity in response to skeletal muscle injury merits further investigation to understand its physiological relevance and potential clinical implications.