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Knee osteoarthritis induces atrophy and neuromuscular junction remodeling in the quadriceps and tibialis anterior muscles of rats.

ABSTRACT: Knee osteoarthritis (KOA) is associated with muscle weakness, but it is unclear which structures are involved in the muscle changes. This study assessed morphological alterations and the expression of genes and proteins linked to muscular atrophy and neuromuscular junctions (NMJs) in KOA, induced by anterior cruciate ligament transection (ACLT) in rats. Two groups of rats were assessed: control (without intervention) and KOA (ACLT surgery in the right knee). After 8 weeks, quadriceps, tibialis anterior (TA) and gastrocnemius muscles were analyzed (area of muscle fibers, NMJ, gene and protein expression). KOA group showed atrophy in quadriceps (15.7%) and TA (33%), with an increase in atrogin-1 and muscle RING-finger protein-1 (MuRF-1). KOA group showed quadriceps NMJ remodeling (reduction area and perimeter) and decrease in NMJ diameter in TA muscle. The expression of nicotinic acetylcholine receptor (nAChR) ?-nAChR increased and that of ?-nAChR and muscle specific tyrosine kinase (MuSK) declined in the quadriceps, with a decrease in ?-nAChR in TA. MuRF-1 protein expression increased in quadriceps and TA, with no changes in neural cell adhesion molecule (NCAM). In conclusion, ACLT-induced KOA promotes NMJ remodeling and atrophy in quadriceps and TA muscles, associated with inflammatory signs and changes in muscle gene and protein expression.

SUBMITTER: Cunha JE

PROVIDER: S-EPMC6482306 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Knee osteoarthritis induces atrophy and neuromuscular junction remodeling in the quadriceps and tibialis anterior muscles of rats.

Cunha Jonathan Emanuel JE Barbosa Germanna Medeiros GM Castro Paula Aiello Tomé de Souza PATS Luiz Beatriz Leite Ferreira BLF Silva Andreza Cristine Arcari ACA Russo Thiago Luiz TL Vasilceac Fernando Augusto FA Cunha Thiago Mattar TM Cunha Fernando Queiróz FQ Salvini Tania Fátima TF

Scientific reports 20190424 1

Knee osteoarthritis (KOA) is associated with muscle weakness, but it is unclear which structures are involved in the muscle changes. This study assessed morphological alterations and the expression of genes and proteins linked to muscular atrophy and neuromuscular junctions (NMJs) in KOA, induced by anterior cruciate ligament transection (ACLT) in rats. Two groups of rats were assessed: control (without intervention) and KOA (ACLT surgery in the right knee). After 8 weeks, quadriceps, tibialis a ...[more]

PMID: 31019213

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Project description:CONTEXT:Relationships between quadriceps function and patient-reported outcomes after anterior cruciate ligament reconstruction (ACLR) are variable and may be confounded by including patients at widely different time points after surgery. Understanding these relationships during the clinically relevant phases of recovery may improve our knowledge of specific factors that influence clinical outcomes. OBJECTIVE:To identify the relationships between quadriceps function and patient-reported outcomes in patients <2 years (early) and >2 years (late) after ACLR, including those with posttraumatic knee osteoarthritis. DESIGN:Cross-sectional study. SETTING:Laboratory. PATIENTS OR OTHER PARTICIPANTS:A total of 72 patients after ACLR: early (n = 34, time from surgery = 9.0 ± 4.3 months), late (n = 30, time from surgery = 70.5 ± 41.6 months), or osteoarthritis (n = 8, time from surgery = 115.9 ± 110.0 months). MAIN OUTCOME MEASURE(S):The total Knee Injury and Osteoarthritis Outcome Score (KOOS) and Veterans RAND 12-Item Health Survey (VR-12) were used to quantify knee function and global health. Predictors of patient-reported outcomes were involved-limb and symmetry indices of quadriceps function (isokinetic strength [peak torque, total work, average power], maximum voluntary isometric contraction torque, fatigue index, central activation ratio, Hoffmann reflex, active motor threshold) and demographics (age, activity level, pain, kinesiophobia, time since surgery). Multiple linear regression analyses were used to predict KOOS and VR-12 scores in each group. RESULTS:In the early patients, knee-extensor work, active motor threshold symmetry, pain, and activity level explained 67.8% of the variance in the KOOS score ( P < .001); knee-extensor work, activity level, and pain explained 53.0% of the variance in the VR-12 score ( P < .001). In the late patients, age and isokinetic torque symmetry explained 28.9% of the variance in the KOOS score ( P = .004). In the osteoarthritis patients, kinesiophobia and isokinetic torque explained 77.8% of the variance in the KOOS score ( P = .010); activity level explained 86.4% of the variance in the VR-12 score ( P = .001). CONCLUSIONS:Factors of muscle function and demographics that explain patient-reported outcomes were different in patients early and late after ACLR and in those with knee osteoarthritis.

Project description:BackgroundSarcopenia is common in patients with Parkinson's disease (PD), showing mitochondrial oxidative stress in skeletal muscle. The aggregation of α-synuclein (α-Syn) to induce oxidative stress is a key pathogenic process of PD; nevertheless, we know little about its potential role in regulating peripheral nerves and the function of the muscles they innervate.MethodsTo investigate the role of α-Syn aggregation on neuromuscular system, we used the Thy1 promoter to overexpress human α-Syn transgenic mice (mThy1-hSNCA). hα-Syn expression was evaluated by western blot, and its localization was determined by confocal microscopy. The impact of α-Syn aggregation on the structure and function of skeletal muscle mitochondria and neuromuscular junctions (NMJs), as well as muscle mass and function were characterized by flow cytometry, transmission electron microscopy, Seahorse XF24 metabolic assay, and AAV9 in vivo injection. We assessed the regenerative effect of mitochondrial-targeted superoxide dismutase (Mito-TEMPO) after skeletal muscle injury in mThy1-hSNCA mice.ResultsOverexpressed hα-Syn protein localized in motor neuron axons and NMJs in muscle and formed aggregates. α-Syn aggregation increased the number of abnormal mitochondrial in the intramuscular axons and NMJs by over 60% (P < 0.01), which inhibited the release of acetylcholine (ACh) from presynaptic vesicles in NMJs (P < 0.05). The expression of genes associated with NMJ activity, neurotransmission and regulation of reactive oxygen species (ROS) metabolic process were significantly decreased in mThy1-hSNCA mice, resulting in ROS production elevated by ~220% (P < 0.05), thereby exacerbating oxidative stress. Such process altered mitochondrial spatial relationships to sarcomeric structures, decreased Z-line spacing by 36% (P < 0.05) and increased myofibre apoptosis by ~10% (P < 0.05). Overexpression of α-Syn altered the metabolic profile of muscle satellite cells (MuSCs), including basal respiratory capacity (~170% reduction) and glycolytic capacity (~150% reduction) (P < 0.05) and decreased cell migration and fusion during muscle regeneration (~60% and ~40%, respectively) (P < 0.05). We demonstrated that Mito-TEMPO treatment could restore the oxidative stress status (the complex I/V protein and enzyme activities increased ~200% and ~150%, respectively), which caused by α-Syn aggregation, and improve the ability of muscle regeneration after injury. In addition, the NMJ receptor fragmentation and ACh secretion were also improved.ConclusionsThese results reveal that the α-synuclein aggregation plays an important role in regulating acetylcholine release from neuromuscular junctions and induces intramuscular mitochondrial oxidative stress, which can provide new insights into the aetiology of muscle atrophy in patients with Parkinson's disease.

Project description:Neuromuscular electrical stimulation (NMES) has been used to increase muscle strength and physical function. However, NMES induces rapid fatigue, limiting its application. To date, the effect of quadriceps femoris (QF) muscle length by knee and hip joint manipulation on NMES-induced contraction fatigability is not clear. We aimed to quantify the effects of different muscle lengths on NMES-induced contraction fatigability, fatigue index, and electromyographic (EMG) activity for QF muscle. QF maximum evoked contraction (QMEC) was applied in a 26 min protocol (10 s on; 120 s off; 12 contractions) in 20 healthy participants (24.0 ± 4.6 years old), over 4 sessions on different days to test different conditions. The tested conditions were as follows: 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). Contraction fatigability (torque decline assessed by maximal voluntary contraction [MVC] and during NMES), fatigue index (percentage reduction in MVC), and EMG activity (root mean square [RMS] and median frequency) of the superficial QF' constituents were assessed. After NMES, all positions except SUP20 had an absolute reduction in MVC (p < .001). Fatigue index was greater in SIT20 than in SIT60 (p < .001) and SUP20 (p = .01). There was significant torque reduction across the 12 QMEC in SUP60 and SIT60, up to 10.5% (p < .001-.005) and 9.49% (p < .001-.033), respectively. There was no torque reduction during NMES in SUP20 and SIT20. Fatigue was accompanied by an increase in RMS (p = .032) and a decrease in median frequency for SUP60 (p < .001). Median frequency increased only in the SUP20 condition (p = .021). We concluded that QF NMES-induced contraction fatigability is greater when the knee is flexed at 60° compared to 20°. In addition, a supine position promotes earlier fatigue for a 60° knee flexion, but it delays fatigue onset for a 20° knee flexion compared to the seated position. These results provide a rationale for lower limb positioning during NMES, which depends on training objectives, e.g., strengthening or task-specific functionality training.

Dataset Information

Knee osteoarthritis induces atrophy and neuromuscular junction remodeling in the quadriceps and tibialis anterior muscles of rats.

Publications

Knee osteoarthritis induces atrophy and neuromuscular junction remodeling in the quadriceps and tibialis anterior muscles of rats.

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