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Aim: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP)., Method: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were analyzed with a focused query investigating metabolism- and mitochondria-related gene networks., Results: The mtDNA to genomic DNA ratio was lower in the children with CP compared to the typically developing group (-23%, p=0.002). Out of five investigated complexes in the mitochondrial respiratory chain, we observed lower protein levels of all complexes (I, III, IV, V, -20% to -37%; p<0.05) except complex II. Total peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) messenger RNA (p<0.004), isoforms PGC1α1 (p=0.05), and PGC1α4 (p<0.001) were reduced in CP. Transcriptional similarities were observed between CP, aging, and 90 days' bed rest., Interpretation: Mitochondrial biogenesis, mtDNA, and oxidative phosphorylation protein content are reduced in CP muscle compared with typically developing muscle. Transcriptional pathways shared between aging and long-term unloading suggests metabolic dysregulation in CP, which may guide therapeutic strategies for combatting CP muscle pathology. What this paper adds Cerebral palsy (CP) muscle contains fewer energy-generating organelles than typically developing muscle. Gene expression in CP muscle is similar to aging and long-term bed rest., (© 2021 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Individuals with cerebral palsy (CP) are less physically active, spend more time sedentary and have lower cardiorespiratory endurance as compared to typically developed individuals. RaceRunning enables high-intensity exercise in individuals with CP with limited or no walking ability, using a three-wheeled running bike with a saddle and a chest plate for support, but no pedals. Training adaptations using this type of exercise are unknown., Methods: Fifteen adolescents/young adults (mean age 16, range 9-29, 7 females/8 males) with CP completed 12 weeks, two sessions/week, of RaceRunning training. Measurements of cardiorespiratory endurance (6-min RaceRunning test (6-MRT), average and maximum heart rate, rate of perceived exertion using the Borg scale (Borg-RPE)), skeletal muscle thickness (ultrasound) of the thigh (vastus lateralis and intermedius muscles) and lower leg (medial gastrocnemius muscle) and passive range of motion (pROM) of hip, knee and ankle were collected before and after the training period., Results: Cardiorespiratory endurance increased on average 34% (6-MRT distance; pre 576 ± 320 m vs. post 723 ± 368 m, p < 0.001). Average and maximum heart rate and Borg-RPE during the 6-MRT did not differ pre vs. post training. Thickness of the medial gastrocnemius muscle increased 9% in response to training (p < 0.05) on the more-affected side. Passive hip flexion increased (p < 0.05) on the less-affected side and ankle dorsiflexion decreased (p < 0.05) on the more affected side after 12 weeks of RaceRunning training., Conclusions: These results support the efficacy of RaceRunning as a powerful and effective training modality in individuals with CP, promoting both cardiorespiratory and peripheral adaptations.

Objective: To investigate the potential of an acute bout of transcranial electrical stimulation to induce anabolic signalling., Design: Experimental intervention on healthy subjects., Subjects: Ten healthy subjects, 5 women and 5 men (mean age (standard deviation (SD) 32 years (SD 4))., Methods: The quadriceps muscle was stimulated at a frequency of 10 Hz for 10 s, followed by 20 s of rest, repeated 40 times over 20 min. Electromyography and force data were collected for all transcranial electrical stimulation sequences. Muscle biopsies were obtained from the vastus lateralis muscle before and 1 and 3 h after stimulation., Results: One bout of transcranial electrical stimulation decreased phosphorylation of AKT at Thr308 (1 h: -29%, 3 h: -38%; p < 0.05) and mTOR phosphorylation at Ser2448 (1 h: -10%; ns, 3 h: -21%; p < 0.05), both in the anabolic pathway. Phosphorylation of AMPK, ACC and ULK1 were not affected. c-MYC gene expression was unchanged following transcranial electrical stimulation, but rDNA transcription decreased (1 h: -28%, 3 h: -19%; p < 0.05). PGC1α-ex1b mRNA increased (1 h: 2.3-fold, 3 h: 2.6-fold; p < 0.05), which also correlated with vastus lateralis electromyography activity, while other PGC-1α variants were unchanged., Conclusion: Acute transcranial electrical stimulation of skeletal muscle in weight-bearing healthy individuals did not induce anabolic signalling, and some signs of impaired muscle anabolism were detected, suggesting limited potential in preventing muscle wasting.

Introduction: Children with cerebral palsy (CP) and acquired brain injury (ABI) commonly develop muscle contractures with advancing age. An underlying growth defect contributing to skeletal muscle contracture formation in CP/ABI has been suggested., Methods: The biceps muscles of children and adolescents with CP/ABI (n = 20) and typically developing controls (n = 10) were investigated. We used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blotting to assess gene expression relevant to growth and size homeostasis., Results: Classical pro-inflammatory cytokines and genes involved in extracellular matrix (ECM) production were elevated in skeletal muscle of children with CP/ABI. Intramuscular collagen content was increased and satellite cell number decreased and this was associated with reduced levels of RNA polymerase I transcription factors, 45s pre-rRNA and 28S rRNA., Discussion: The present study provides novel data suggesting a role for pro-inflammatory cytokines and reduced ribosomal production in the development/maintenance of muscle contractures, possibly underlying stunted growth and perimysial ECM expansion. Muscle Nerve 58: 277-285, 2018., (© 2018 Wiley Periodicals, Inc.)

Muscle and joint contact force influence stresses at the proximal growth plate of the femur and thus bone growth, affecting the neck shaft angle (NSA) and femoral anteversion (FA). This study aims to illustrate how different muscle groups' activation during gait affects NSA and FA development in able-bodied children. Subject-specific femur models were developed for three able-bodied children (ages 6, 7, and 11 years) using magnetic resonance images. Contributions of different muscle groups-hip flexors, hip extensors, hip adductors, hip abductors, and knee extensors-to overall hip contact force were computed. Specific growth rate for the growth plate was computed, and the growth was simulated in the principal stress direction at each element in the growth front. The predicted growth indicated decreased NSA and FA (of about [Formula: see text] over a four-month period) for able-bodied children. Hip abductors contributed the most, and hip adductors, the least, to growth rate. All muscles groups contributed to a decrease in predicted NSA ([Formula: see text]0.01[Formula: see text]-0.04[Formula: see text] and FA ([Formula: see text]0.004[Formula: see text]-[Formula: see text]), except hip extensors and hip adductors, which showed a tendency to increase the FA ([Formula: see text]0.004[Formula: see text]-[Formula: see text]). Understanding influences of different muscle groups on long bone growth tendency can help in treatment planning for growing children with affected gait.

Lower extremity deformities of patients with arthrogryposis multiplex congenita present a wide spectrum of severity and deformity combinations. Treatment goals range from merely ensuring comfortable seating and shoe wear, to fully independent and active ambulation, but the overarching intention is to help realize the patient's greatest potential for independence and function. Treatment of hip and knee contractures and dislocations has become more interventional, whereas treatment of foot deformities has paradoxically become much less surgical. This article synopsizes the treatment strategies presented in September 2014 in Saint Petersburg, Russia at the second international symposium on arthrogryposis.

Background: Children with cerebral palsy (CP) use their paretic arm less than normal but have a relative overactivity of wrist flexors, causing an impairing flexed position of the wrist. Voluntary use of a muscle downregulates myosin heavy chain (MyHC) IIx, but it is unclear whether the relative overactivity of wrist flexors and extensors in children with CP affects MyHC expression compared to normal subjects., Questions/purposes: We therefore asked whether MyHC expression composition differs in wrist flexors compared to extensors in children with CP and in controls and whether it is related to clinical findings., Methods: We took muscle biopsies from wrist flexors and extensors during hand surgery in children with CP (n = 9) and during open reduction of forearm fractures in control children (n = 5). The expression of the MyHC I, IIa, and IIx isoforms were determined on silver-stained 6% SDS-PAGE., Results: CP flexors showed a higher proportion of MyHC IIx (40%) than control flexors (16%) and CP extensors (20%). MyHC IIa isoform proportion was lower in CP flexors (27%) than in control flexors (46%) and in CP extensors (45%). MyHC I expression was lower in CP (36%) than in controls (46%) for wrist extensors only., Conclusions: Both the brain injury in CP and the different demands on flexors and extensors affect the expression of MyHCs. The higher amount of MyHC IIx in CP could be caused by a decreased voluntary use of the hemiplegic arm., Clinical Relevance: More information on the structural difference between flexors and extensors in normal and spastic muscle could improve the understanding of strain of wrist extensors and possibly the development of flexion contractures in CP.

Spastic cerebral palsy can be divided into diagnostic groups by the relative severity of the arm impairment. This study investigates if hemiplegic, tetraplegic or diplegic cerebral palsy (CP) results in different patterns of myosin heavy chain (MyHC) expression in the flexor carpi ulnaris muscle from 17 young patients with CP. Using enzyme-immunohistochemistry and gel electrophoresis techniques we found a higher percentage of fibers expressing fast MyHC IIx (52%) in tetraplegic CP compared to hemiplegic patients (32%), (p<0.05). Tetraplegic CP also resulted in a lower amount of fibers expressing slow MyHC I (18%) compared to hemiplegic CP (40%), (p<0.005). The proportion of muscle fibers containing fetal MyHC was higher in tetraplegic CP compared to other groups, (p<0.005). Taken together theses results indicate that tetraplegic CP is associated with a shift from slow to fast myosins and that regenerative events are more prominent in tetraplegic CP compared with milder brain damage.

Rabbits were immobilized for 3 weeks with the ankle in plantar flexion, midrange position or dorsal extension (n=15). The left leg was used as control. Sarcomere lengths were measured by laser diffraction in vivo in the tibialis anterior (TA) muscle. Legs immobilized in the midrange position showed coherent diffraction patterns through the range of motion, but in those immobilized with TA in the stretched position no diffraction patterns in vivo could be obtained. Morphological analyses revealed increased fibrosis and occurrence of whorled fibers in these muscles. On 15 more likewise immobilized rabbits, a technique of measuring sarcomere lengths in vitro by first digesting the collagen in nitric acid was developed. These in vitro measurements showed shorter sarcomeres in the muscles immobilized in a lengthened position compared to the control, indicating an addition of sarcomeres in series.

Children with cerebral palsy often have spasticity of both the extensors and flexors, but how and why a flexion contracture of the wrist will develop during growth is not thoroughly understood. In order to understand the muscle adaptations that occur during contracture formation, the relationship between intraoperative sarcomere length and the extent of contracture was measured in 23 children (average age, 14.3 +/- 2.9 years) undergoing tendon transfers involving the flexor carpi ulnaris (FCU) or extensor carpi radialis brevis (ECRB) muscles. For both ECRB and FCU, sarcomere lengths measured intraoperatively were longer compared to sarcomere lengths predicted from a regression relationship obtained from "control" patients with radial nerve injury (P < 0.001). The most interesting aspect of the long FCU sarcomere lengths measured was that there was a highly significant correlation between the degree of contracture formation and intraoperative sarcomere length (r2 = 0.5, P < 0.005). These data clearly show that greater contracture severity is associated with longer intraoperative FCU sarcomere length. No such correlation was observed for the ECRB. The data suggest that the clinical presentation of the contracture is related to degree of FCU, but not ECRB adaptation, to the central nervous system lesion.

Morphological properties of skeletal muscle were compared between wrist flexors and extensors within the same children (n = 8, six females, two males; age range 4 to 9y, median age 7 y) with wrist muscle imbalance secondary to spastic cerebral palsy (CP). Five patients had hemiplegic CP, two diplegic CP, and one patient had tetraplegic CP. Muscle biopsies were taken during either tendon transfer or tendon lengthening procedures. Analyses included distribution of muscle fibre types, fibre sizes, and expression of developmental myosins. Extensor fibre area was significantly greater than flexor fibre area for type 2A fibres and type 2B fibres but not for type 1 fibres. Coefficient of variation (CV) of fibre size for all three fibre types was greater for flexors compared with extensors. The greatest CV was observed for the type 2A fibres in flexors (39.5 [3.6%]). A wide variation was observed for expression of developmental myosin with the magnitude of the expression being greater, but not statistically significant, in flexors compared with extensors (5.4/mm2 vs 0.53/mm2). These data demonstrate that significant secondary myopathy of wrist flexor muscles results from CP.