Ferdinand von Walden

Cerebral palsy (CP) is an early-onset neurodevelopmental condition associated with metabolic impairment and an increased risk of non-communicable diseases across the lifespan. However, the basis of these changes remains largely unknown. This study provides a comprehensive cardiometabolic and physical function profile of 23 adults with CP relative to 33 typically developing (TD) adolescents and 61 TD adults. Compared to TD individuals, adults with CP exhibited reduced cardiorespiratory fitness, smaller cardiac dimensions, and lower muscle mass. Circulating metabolomic and proteomic profiling identified a distinct molecular signature in CP, including altered tricarboxylic acid (TCA) cycle metabolites, and elevated myostatin, matrix-related proteins and pro-inflammatory cytokines. We further tested the capacity for physiological and molecular adaptation using an acute bout of endurance exercise. In response to exercise, individuals with CP exhibited an attenuated response compared to TD groups, characterized by a blunted lactate response and lower venous oxygen levels. TD participants also increased canonical exercise-responsive factors, including NADK, IL-8, ANGPTL1 and GDF15, whereas these responses were attenuated in CP. These novel findings define a distinct cardiometabolic profile in adults with CP at rest and reveal an attenuated molecular response to exercise. These data carry implications for targeted interventions and prevention strategies across the lifespan.

Objective: To synthesize evidence on the physiological determinants of endurance capacity in individuals with cerebral palsy. Design: Narrative review. Subjects/Patients: Children and adults with cerebral palsy across the spectrum of motor function (Gross Motor Function Classification System I–V). Methods: Relevant literature on cardiovascular, pulmonary, haematological, and musculoskeletal determinants of endurance capacity in individuals with cerebral palsy was identified and synthesized. Results: Reduced cardiorespiratory fitness is common, with autonomic dysregulation potentially constraining heart rate responses during exercise, while lower oxygen pulse suggests limitations in stroke volume and peripheral oxygen extraction. Restrictive ventilatory patterns, including reduced functional lung volumes, may further impair exercise capacity. High energetic demands during basic movements exacerbate fatigue and reduce engagement in physical activity. Skeletal muscle also exhibits structural and metabolic alterations, including reduced muscle volume, capillary density, and mitochondrial function, impairing oxygen utilization and energy production. Conclusion: Despite methodological heterogeneity, evidence consistently indicates that integrated central and peripheral factors constrain endurance capacity, with impairments more pronounced in individuals with greater functional limitations. Adapted training modalities, such as Frame Running, show promise in improving these outcomes. Understanding these physiological determinants is essential for developing individualized interventions to improve function, participation, health, and quality of life in individuals with cerebral palsy.

Aim: To explore lower leg muscle morphology and intramuscular fat content changes using magnetic resonance imaging (MRI) after 12 months of treatment‐as‐usual (TAU), after the first botulinum neurotoxin A (BoNT‐A) injection in children with cerebral palsy (CP) naive to muscle tone reduction treatment. Method: This prospective longitudinal study included 10 children with spastic CP (five female, median age 8 years 11 months, unilateral CP/bilateral CP 7/3, Gross Motor Function Classification System levels I/II 8/2) and 10 typically developing peers (seven female, median age 9 years 6 months). Children with CP received two MRI scans (before and 12 months after the first injection), typically developing peers received one. Muscle volume (normalized by product of weight and height), fascicle length (normalized by height), pennation angle, and intramuscular fat fraction (IFF) of medial gastrocnemius, lateral gastrocnemius, soleus, and tibialis anterior were quantified. Results: After 12 months of TAU, normalized muscle volume remained unchanged while IFF increased (medial gastrocnemius: p = 0.008). Compared to typically developing peers, children with CP had smaller normalized muscle volume (tibialis anterior: p = 0.027) and similar IFF at pre‐injection timepoint. Interpretation: Although normalized muscle volume remained unchanged after the 12‐month TAU, concurrent fat infiltration was evident in medial gastrocnemius.

Our findings establish ribosome biogenesis and ribosome remodeling as core components of the skeletal muscle regenerative program conserved across species. The rapid, MYC-driven induction of translational capacity, coupled with a transient switch in ribosomal protein composition, increases ribosome heterogeneity during skeletal muscle regeneration.

Regular exercise using assistive movement devices, such as running frames, has emerged as a promising strategy to improve cardiorespiratory fitness in individuals with cerebral palsy (CP). However, the molecular pathways underlying these adaptations remain poorly understood. Here, we examined a novel class of signalling molecules, mitochondrial‐derived microproteins (MDPs), and assessed whether individuals with CP exhibit altered circulating levels compared with typically developing (TD) individuals at rest and following an acute bout of endurance exercise. Three groups were included: TD adults (31 ± 6 years), TD adolescents (16 ± 1 years) and adults with CP (25 ± 6 years). Individuals with CP were classified as Gross Motor Function Classification System (GMFCS) levels II−IV and had at least 3 months of frame running experience. Habitual physical activity, ultrasound‐derived muscle thickness, and peak oxygen uptake were assessed. The exercise session consisted of 45 min of frame running for individuals with CP and conventional running for TD participants. Blood samples were obtained before and 1 h after exercise, and plasma MDP concentrations were measured using in‐house enzyme‐linked immunosorbent assay. Adults with CP had reduced muscle mass and maximal oxygen uptake compared to TD individuals. Despite this, they exhibited basal circulating levels of MDPs, including humanin, MOTS‐c and SHMOOSE, comparable to TD adults and adolescents, with no associations with CP subtype or motor impairment severity. Following exercise, circulating MDPs showed no or only modest changes across groups, with no differences between CP and TD individuals. Overall, these findings suggest preserved mitochondrial‐derived signalling via MDPs in individuals with CP.

Cerebral palsy (CP) is the most common cause of childhood‐onset physical disability. It results from injury to the developing brain and is characterized by motor impairments, muscle weakness, and fatigue. CP is commonly associated with marked deficits in muscle mass and function, and many individuals experience early declines in physical performance and functional ability as they age. These features resemble changes observed in age‐related muscle loss, that is, sarcopenia, raising the possibility of shared underlying mechanisms. This paper hypothesizes that skeletal muscles of individuals with CP undergo accelerated aging, driven by cellular and molecular pathways similar to those implicated in sarcopenia. To support this hypothesis, we highlight emerging evidence of phenotypic overlap between CP and aging muscle, including neuromuscular changes, impaired satellite cell function, altered niche components, chronic inflammation, and metabolic deficits such as reduced capillarization and mitochondrial dysfunction. To test this hypothesis, we propose cross‐sectional and longitudinal studies targeting both baseline aging markers and the rate of aging‐related changes. These studies should focus on established hallmarks of aging, such as mitochondrial dysfunction, DNA methylation, and markers of cellular senescence. If confirmed, this hypothesis could reshape our understanding of muscle pathology in CP. It may also open up the possibility of repurposing therapeutic strategies demonstrated to be effective in geriatric care for children and young adults with CP.

Introduction/Aims: Traditional methods of sampling skeletal muscle tissue are invasive. This study aimed to evaluate a sub‐millimeter core‐biopsy (microbiopsy) as a potentially more tolerable method, with further regard to tissue yield and analyzability of RNA expression. Methods: Children (9–13 years, n = 11) and adults (18–50 years, n = 16) were recruited. Microbiopsy and venipuncture were performed, with prior application of local anesthesia cream. Additionally, adults underwent a Bergström muscle biopsy, with infiltrative local anesthesia. Pain was rated using the visual analog scale (VAS), reported as medians (95% CI). Microbiopsy samples were freeze‐dried and weighed. To evaluate RNA sequencing performance at low tissue sample weights, a six‐step incremental tissue ladder (10–500 μg) was analyzed. Results: Children rated venipunctures and microbiopsies low, at VAS = 0.1 (0.0–0.6) and 1.6 (0.9–3.9), respectively. Microbiopsy pain ratings were slightly higher than venipuncture, p < 0.001. Pain ratings in adults were 0.0 (0.0–0.5), 1.8 (1.3–2.4), 2.9 (2.4–3.8), and 2.7 (2.2–3.8) for venipuncture, microbiopsy, Bergström biopsy, and infiltrative local anesthesia, respectively. Microbiopsy was rated less painful than Bergström biopsy and local anesthesia ( p < 0.05). Children did not rate microbiopsy more painful than adults ( p = 0.82). Microbiopsies yielded on average 303 (SD 121.8) μg. RNA sequencing detected similar transcriptomic signatures across the tissue ladder. Discussion: The generally low pain ratings for the microbiopsy procedure support its use as a tolerable method of acquiring skeletal muscle samples in both children and adults. It represents a less painful alternative to Bergström biopsies while still rendering adequate material for RNA sequencing.

Aim: To explore the integrated cardiopulmonary, metabolic, and muscular response to incremental exercise in individuals with cerebral palsy (CP) compared with typically developing participants. Method: This was a prospective cross‐sectional study. Sixteen (seven male) individuals with CP (classified in Gross Motor Function Classification System levels II–V) and 30 (15 male) typically developing participants performed a treadmill‐based incremental submaximal test and an exercise test to task failure. Participants used running frames (CP) or performed traditional running (typically developing participants). Metabolic and cardiopulmonary parameters were measured during both tests. Electromyography of the vastus lateralis and gastrocnemius medialis was recorded during the test to task failure. Results: Compared with typically developing participants, individuals with CP showed decreased minute ventilation ( p < 0.05), increased respiratory frequency at a comparable exercise intensity ( p < 0.05), and an altered metabolic response, on the basis of the partial pressure of carbon dioxide ( p < 0.05) and lactate levels ( p < 0.001), during both tests. In addition, participants with CP exhibited a lower ventilatory efficiency during the test to task failure ( p < 0.01). Electromyography analysis suggested peripheral skeletal muscle fatigue in the lower limbs ( p < 0.05) in individuals with CP compared with typically developing participants. Interpretation: Individuals with CP have a disproportional ventilatory response to incremental exercise, not driven by metabolic perturbations. The increased breathing frequency resulted in high rate of perceived exertion and signs of peripheral muscle fatigue compared with typically developing participants. Our findings stress the importance of interventions focused on ventilatory function in individuals with CP.

Cerebral palsy (CP), the most prevalent childhood‐onset motor disability, frequently entails progressive musculoskeletal complications. This comprehensive review synthesizes existing knowledge of microscopic and molecular alterations in CP skeletal muscle. Considerable methodological variability, heterogeneous patient cohorts, and inconsistent control groups significantly complicate comparative interpretations across studies. Nonetheless, some structural abnormalities consistently emerge, including increased variability in muscle fibre size, altered fibre type distribution, long sarcomeres at standardized joint positions, increased collagen content, disrupted neuromuscular junction integrity, reduced capillary density, and mitochondrial and satellite cell impairments. Investigations of satellite cell function in vitro further underscore potential mechanistic alterations, although findings remain inconsistent. Remarkably, few studies have systematically explored the cellular and molecular consequences of standard clinical interventions, revealing a notable research gap. In conclusion, the overall literature reveals considerable divergence in reported outcomes, reflecting the profound complexity of CP muscle biology. We believe that resolving this complexity will require more coordinated and collaborative research approaches.