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Following injury, skeletal muscle undergoes repair via satellite cell (SC)-mediated myogenic progression. In SCs, the circadian molecular clock gene, Bmal1, is necessary for appropriate myogenic progression and repair with evidence that muscle molecular clocks can also affect force production. Utilizing a mouse model allowing for inducible depletion of Bmal1 within SCs, we determined contractile function, SC myogenic progression and muscle damage and repair following eccentric contractile-induced injury. At baseline, SC-Bmal1 iKO animals exhibited a ~20-25% reduction in normalized force production (ex vivo and in vivo) versus control SC-Bmal1 Cntrl and SC-Bmal1 iKO untreated littermates (p < .05). Following contractile injury, SC-Bmal1 iKO animals displayed reduced muscle damage and subsequent repair post-injury (Dystrophin negative fibers 24 h: SC-Bmal1 Cntrl 199 ± 41; SC-Bmal1 iKO 36 ± 13, p < .05) (eMHC + fibers 7 day: SC-Bmal1 Cntrl 217.8 ± 115.5; SC-Bmal1 iKO 27.8 ± 17.3; Centralized nuclei 7 day: SC-Bmal1 Cntrl 160.7 ± 70.5; SC-Bmal1 iKO 46.2 ± 15.7). SC-Bmal1 iKO animals also showed reduced neutrophil infiltration, consistent with less injury (Neutrophil content 24 h: SC-Bmal1 Cntrl 2.4 ± 0.4; SC-Bmal1 iKO 0.4 ± 0.2, % area fraction, p < .05). SC-Bmal1 iKO animals had greater SC activation/proliferation at an earlier timepoint (p < .05) and an unexplained increase in activation 7 days post injury. Collectively, these data suggest SC-Bmal1 plays a regulatory role in force production, influencing the magnitude of muscle damage/repair, with an altered SC myogenic progression following contractile-induced muscle injury., (© 2025 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Mitochondrial abnormalities exist in lower-extremity peripheral artery disease (PAD), yet the association of the ankle-brachial index (ABI) with mitochondrial respiration in gastrocnemius muscle is unknown. The association of gastrocnemius mitochondrial respiration with 6-minute walk distance in PAD is unknown. This objective of this study was to describe associations of the ABI with mitochondrial respiratory function in gastrocnemius muscle biopsies and associations of gastrocnemius mitochondrial respirometry with 6-minute walk distance in people with and without PAD., Methods: People with (ABI ⩽ 0.90) and without (ABI 1.00-1.40) PAD were enrolled. ABI and 6-minute walk distance were measured. Mitochondrial function of permeabilized myofibers from gastrocnemius biopsies was measured with high-resolution respirometry., Results: A total of 30 people with PAD (71.7 years, mean ABI: 0.64) and 68 without PAD (71.8 years, ABI: 1.17) participated. In non-PAD participants, higher ABI values were associated significantly with better mitochondrial respiration (Pearson correlation for maximal oxidative phosphorylation P CI+II : +0.29, p = 0.016). In PAD, the ABI correlated negatively and not significantly with mitochondrial respiration (Pearson correlation for P CI+II : -0.17, p = 0.38). In people without PAD, better mitochondrial respiration was associated with better 6-minute walk distance (Pearson correlation: +0.51, p < 0.001), but this association was not present in PAD (Pearson correlation: +0.10, p = 0.59)., Conclusions: Major differences exist between people with and without PAD in the association of gastrocnemius mitochondrial respiration with ABI and 6-minute walk distance. Among people without PAD, ABI and walking performance were positively associated with mitochondrial respiratory function. These associations were not observed in PAD., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. McDermott has received research support from Helixmith, Mars, and ArtAssist. The other authors have no conflicts of interest.

Aim: To evaluate whether serum metabolomics differ between ambulatory individuals with cerebral palsy (CP) compared with individuals with typical development and whether functional capacity is associated with metabolite abundance., Method: Thirty-eight adolescents and young adults were enrolled (CP: n = 19; typical development: n = 19). After functional capacity testing (10-meter walk, sit-to-stand, and peak knee flexion/extension torques), blood was drawn. Targeted serum metabolomics on hydrophilic metabolites were performed by high-performance liquid chromatography coupled with high-resolution and tandem mass spectrometry. Metabolite dimensionality reduction, pathway analysis, fold change, and t-tests evaluated changes in metabolite abundance. Associations were tested between functional measures and metabolite abundance., Results: Individuals with CP had a significant increase in the abundance of essential amino acids, catabolic products of protein metabolism, and tricarboxylic acid cycle substrates, such as valine, tryptophan, kynurenic acid, and pyruvate (p < 0.05). Importantly, the abundance of numerous metabolites was only highly associated with functional capacity in individuals with CP such that greater abundance was associated with greater capacity, but not in those with typical development., Interpretation: Our findings show clear increases in serum metabolites in individuals with CP, which are associated with functional capacity for movement. The altered metabolite profile measured after exercise might reflect increased energy production needed for movement. Appropriate nutritional intake during exercise might be needed given increased energy requirements., (© 2024 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Muscle isometric torque fluctuates according to time-of-day with such variation owed to the influence of circadian molecular clock genes. Satellite cells (SCs), the muscle stem cell population, also express molecular clock genes with several contractile-related genes oscillating in a diurnal pattern. Currently, limited evidence exists regarding the relationship between SCs and contractility, although long-term SC ablation alters muscle contractile function. Whether there are acute alterations in contractility following SC ablation and with respect to the time-of-day is unknown. We investigated whether short-term SC ablation affected contractile function at two times of day and whether any such alterations led to different extents of eccentric contraction-induced injury. Using an established mouse model to deplete SCs, we characterized muscle clock gene expression and ex vivo contractility at two times-of-day (morning: 0700 and afternoon: 1500). Morning-SC + animals demonstrated ∼25%-30% reductions in tetanic/eccentric specific forces and, after eccentric injury, exhibited ∼30% less force-loss and ∼50% less dystrophin negative fibers versus SC - counterparts; no differences were noted between Afternoon groups (Morning-SC + : -5.63 ± 0.61, Morning-SC - : -7.93 ± 0.61; N/cm 2 ; P < 0.05) (Morning-SC + : 32 ± 2.1, Morning-SC - : 64 ± 10.2; dystrophin negative fibers; P < 0.05). As Ca ++ kinetics underpin force generation, we also evaluated caffeine-induced contracture force as an indirect marker of Ca ++ availability and found similar force reductions in Morning-SC + vs. SC - mice. We conclude that force production is reduced in the presence of SCs in the morning but not in the afternoon, suggesting that SCs may have a time-of-day influence over contractile function. NEW & NOTEWORTHY Muscle isometric torque fluctuates according to time-of-day with such variation owed to molecular clock regulation. Satellite cells (SCs) have recently demonstrated diurnal characteristics related to muscle physiology. In our work, force production was reduced in the presence versus absence of SCs in the morning but, not in the afternoon. Morning-SC + animals, producing lower force, sustained lesser degrees of injury versus SC - counterparts. One potential mechanism underpinning lower forces produced appears to be lower calcium availability.

Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions successfully arrest age-related muscle impairments since the decline is frequently multifactorial. Previously, we found that systemic transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) isolated from young mice-but not old-extends the health-span in DNA damage mouse models of progeria, a disease of accelerated aging. Additionally, induced neovascularization in the muscles and brain-where no transplanted cells were detected-strongly suggests a systemic therapeutic mechanism, possibly activated through circulating secreted factors. Herein, we used ZMPSTE24-deficient mice, a lamin A defect progeria model, to investigate the ability of young MDSPCs to preserve neuromuscular tissue structure and function. We show that progeroid ZMPST24-deficient mice faithfully exhibit sarcopenia and age-related metabolic dysfunction. However, systemic transplantation of young MDSPCs into ZMPSTE24-deficient progeroid mice sustained healthy function and histopathology of muscular tissues throughout their 6-month life span in a sex-specific manner. Indeed, female-but not male-mice systemically transplanted with young MDSPCs demonstrated significant preservation of muscle endurance, muscle fiber size, mitochondrial respirometry, and neuromuscular junction morphometrics. These novel findings strongly suggest that young MDSPCs modulate the systemic environment of aged animals by secreted rejuvenating factors to maintain a healthy homeostasis in a sex-specific manner and that the female muscle microenvironment remains responsive to exogenous regenerative cues in older age. This work highlights the age- and sex-related differences in neuromuscular tissue degeneration and the future prospect of preserving health in older adults with systemic regenerative treatments., (© 2023. The Author(s).)

Physical activity of a sufficient amount and intensity is essential to health and the prevention of a sedentary lifestyle in all children as they transition into adolescence and adulthood. While fostering a fit lifestyle in all children can be challenging, it may be even more so for those with cerebral palsy (CP). Evidence suggests that bone and muscle health can improve with targeted exercise programs for children with CP. Yet, it is not clear how musculoskeletal improvements are sustained into adulthood. In this perspective, we introduce key ingredients and guidelines to promote bone and muscle health in ambulatory children with CP (GMFCS I-III), which could lay the foundation for sustained fitness and musculoskeletal health as they transition from childhood to adolescence and adulthood. First, one must consider crucial characteristics of the skeletal and muscular systems as well as key factors to augment bone and muscle integrity. Second, to build a better foundation, we must consider critical time periods and essential ingredients for programming. Finally, to foster the sustainability of a fit lifestyle, we must encourage commitment and self-initiated action while ensuring the attainment of skill acquisition and function. Thus, the overall objective of this perspective paper is to guide exercise programming and community implementation to truly alter lifelong fitness in persons with CP.

Skeletal muscle comprises approximately 50% of individual body mass and plays vital roles in locomotion, heat production, and whole body metabolic homeostasis. This tissue exhibits a robust diurnal rhythm that is under control of the suprachiasmatic nucleus (SCN) region of the hypothalamus. The SCN acts as a "central" coordinator of circadian rhythms, while cell-autonomous "peripheral" clocks are located within almost all other tissues/organs in the body. Synchronization of the peripheral clocks in muscles (and other tissues) together with the central clock is crucial to ensure temporally coordinated physiology across all organ systems. By virtue of its mass, human skeletal muscle contains the largest collection of peripheral clocks, but within muscle resides a local stem cell population, satellite cells (SCs), which have their own functional molecular clock, independent of the numerous muscle clocks. Skeletal muscle has a daily turnover rate of 1%-2%, so the regenerative capacity of this tissue is important for whole body homeostasis/repair and depends on successful SC myogenic progression (i.e., proliferation, differentiation, and fusion). Emerging evidence suggests that SC-mediated muscle regeneration may, in part, be regulated by molecular clocks involved in SC-specific diurnal transcription. Here we provide insights on molecular clock regulation of muscle regeneration/repair and provide a novel perspective on the interplay between SC-specific molecular clocks, myogenic programs, and cell cycle kinetics that underpin myogenic progression.

Background Mitochondrial abnormalities exist in gastrocnemius muscle of people with peripheral artery disease (PAD). Whether abnormalities in mitochondrial biogenesis and autophagy are associated with greater ischemia or walking impairment in PAD is unknown. Methods and Results Protein markers of mitochondrial biogenesis and autophagy and the abundance of mitochondrial electron transport chain complexes were quantified in gastrocnemius muscle biopsies from people with and without PAD. Their 6-minute walk distance and 4-m gait speed were measured. Sixty-seven participants (mean age 65.0 years [±6.8], 16 [23.9%] women, 48 [71.6%] Black) were enrolled, including 15 with moderate to severe PAD (ankle brachial index [ABI] <0.60), 29 with mild PAD (ABI 0.60-0.90), and 23 without PAD (ABI 1.00-1.40). Abundance of all electron transport chain complexes was significantly higher in participants with lower ABI (eg, complex I: 0.66, 0.45, 0.48 arbitrary units [AU], respectively, P trend=0.043). Lower ABI values were associated with a higher LC3A/B II-to-LC3A/B I (microtubule-associated protein 1A/1B-light chain 3) ratio (2.54, 2.31, 2.15 AU, respectively, P trend=0.017) and reduced abundance of the autophagy receptor p62 (0.71, 0.69, 0.80 AU, respectively, P trend=0.033). The abundance of each electron transport chain complex was positively and significantly associated with 6-minute walk distance and 4-m gait speed at usual and fast pace only among participants without PAD (eg, complex I: r =0.541, P =0.008; r =0.477, P =0.021; r =0.628, P =0.001, respectively). Conclusions These results suggest that accumulation of electron transport chain complexes in gastrocnemius muscle of people with PAD may be because of impaired mitophagy in the setting of ischemia. Findings are descriptive, and further study in larger sample sizes is needed.

Children with cerebral palsy (CP), a perinatal brain alteration, have impaired postnatal muscle growth, with some muscles developing contractures. Functionally, children are either able to walk or primarily use wheelchairs. Satellite cells are muscle stem cells (MuSCs) required for postnatal development and source of myonuclei. Only MuSC abundance has been previously reported in contractured muscles, with myogenic characteristics assessed only in vitro. We investigated whether MuSC myogenic, myonuclear, and myofiber characteristics in situ differ between contractured and noncontractured muscles, across functional levels, and compared with typically developing (TD) children with musculoskeletal injury. Open muscle biopsies were obtained from 36 children (30 CP, 6 TD) during surgery; contracture correction for adductors or gastrocnemius, or from vastus lateralis [bony surgery in CP, anterior cruciate ligament (ACL) repair in TD]. Muscle cross sections were immunohistochemically labeled for MuSC abundance, activation, proliferation, nuclei, myofiber borders, type-1 fibers, and collagen content in serial sections. Although MuSC abundance was greater in contractured muscles, primarily in type-1 fibers, their myogenic characteristics (activation, proliferation) were lower compared with noncontractured muscles. Overall, MuSC abundance, activation, and proliferation appear to be associated with collagen content. Myonuclear number was similar between all muscles, but only in contractured muscles were there associations between myonuclear number, MuSC abundance, and fiber cross-sectional area. Puzzlingly, MuSC characteristics were similar between ambulatory and nonambulatory children. Noncontractured muscles in children with CP had a lower MuSC abundance compared with TD-ACL injured children, but similar myogenic characteristics. Contractured muscles may have an intrinsic deficiency in developmental progression for postnatal MuSC pool establishment, needed for lifelong efficient growth and repair.

Background: This study evaluated the association of smoking with mitochondrial function in gastrocnemius muscle of people with peripheral artery disease (PAD)., Methods: Participants were enrolled from Chicago, Illinois and consented to gastrocnemius biopsy. Mitochondrial oxidative capacity was measured in muscle with respirometry. Abundance of voltage-dependent anion channel (VDAC) (mitochondrial membrane abundance), peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) (mitochondrial biogenesis), and electron transport chain complexes I-V were measured with Western blot., Results: Fourteen of 31 people with PAD (age 72.1 years, ABI 0.64) smoked cigarettes currently. Overall, there were no significant differences in mitochondrial oxidative capacity between PAD participants who currently smoked and those not currently smoking (complex I+II-mediated oxidative phosphorylation: 86.6 vs 78.3 pmolO 2 /s/mg, respectively [ p = 0.39]). Among participants with PAD, those who currently smoked had a higher abundance of PGC-1α ( p < 0.01), VDAC ( p = 0.022), complex I ( p = 0.021), and complex III ( p = 0.021) proteins compared to those not currently smoking. People with PAD who currently smoked had lower oxidative capacity per VDAC unit (complex I+II-mediated oxidative phosphorylation [137.4 vs 231.8 arbitrary units, p = 0.030]) compared to people with PAD not currently smoking. Among people without PAD, there were no significant differences in any mitochondrial measures between currently smoking ( n = 5) and those not currently smoking ( n = 63)., Conclusions: Among people with PAD, cigarette smoking may stimulate mitochondrial biogenesis to compensate for reduced oxidative capacity per unit of mitochondrial membrane, resulting in no difference in overall mitochondrial oxidative capacity according to current smoking status among people with PAD. However, these results were cross-sectional and a longitudinal study is needed.

Aim: To compare skeletal muscle mitochondrial enzyme activity and mitochondrial content between independently ambulatory children with cerebral palsy (CP) and typically developing children., Method: Gracilis biopsies were obtained from 12 children during surgery (n=6/group, children with CP: one female, five males, mean age 13y 4mo, SD 5y 1mo, 4y 1mo-17y 10mo; typically developing children: three females, three males, mean age 16y 5mo, SD 1y 4mo, 14y 6mo-18y 2mo). Spectrophotometric enzymatic assays were used to evaluate the activity of mitochondrial electron transport chain complexes. Mitochondrial content was evaluated using citrate synthase assay, mitochondrial DNA copy number, and immunoblots for specific respiratory chain proteins., Results: Maximal enzyme activity was significantly (50-80%) lower in children with CP versus typically developing children, for complex I (11nmol/min/mg protein, standard error of the mean [SEM] 1.7 vs 20.7nmol/min/mg protein, SEM 4), complex II (6.9nmol/min/mg protein, SEM 1.2 vs 21nmol/min/mg protein, SEM 2.7), complex III (31.9nmol/min/mg protein, SEM 7.4 vs 72.7nmol/min/mg protein, SEM 7.2), and complex I+III (7.4nmol/min/mg protein, SEM 2.5 vs 31.8nmol/min/mg protein, SEM 9.3). Decreased electron transport chain activity was not the result of lower mitochondrial content., Interpretation: Skeletal muscle mitochondrial electron transport chain enzymatic activity but not mitochondrial content is reduced in independently ambulatory children with CP. Decreased mitochondrial oxidative capacity might explain reported increased energetics of movement and fatigue in ambulatory children with CP. What this paper adds Skeletal muscle mitochondrial electron transport chain enzymatic activity is reduced in independently ambulatory children with cerebral palsy (CP). Mitochondrial content appears to be similar between children with CP and typically developing children., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Individuals with cerebral palsy (CP) report physical fatigue as a main cause of limitation, deterioration and eventually cessation of their walking ability. A consequence of higher level of fatigue in individuals with CP leads to a less efficient and long-distance walking ability., Research Question: This systematic review investigates the difference in 1) walking energy expenditure between individuals with CP and age-matched typically developing (TD) individuals; and 2) energetics of walking across Gross Motor Function Classification System (GMFCS) levels and age., Methods: Five electronic databases (PubMed, Web of Science, CINAHL, ScienceDirect and Scopus) were searched using search terms related to CP and energetics of walking., Results: Forty-one studies met inclusion criteria. Thirty-one studies compared energy expenditure between CP and age-matched controls. Twelve studies correlated energy expenditure and oxygen cost across GMFCS levels. Three studies investigated the walking efficiency across different ages or over a time period. A significant increase of energy expenditure and oxygen cost was found in individuals with CP compared to TD age-matched individuals, with a strong relationship across GMFCS levels., Significance: Despite significant differences between individuals with CP compared to TD peers, variability in methods and testing protocols may play a confounding role. Analysis suggests oxygen cost being the preferred/unbiased physiological parameter to assess walking efficacy in CP. To date, there is a knowledge gap on age-related changes of walking efficiency across GMFCS levels and wider span of age ranges. Further systematic research looking at longitudinal age-related changes of energetics of walking in this population is warranted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Satellite cells (SCs) are quiescent, adult skeletal muscle stem cells responsible for postnatal muscle growth and repair. Children with cerebral palsy (CP) have muscle contractures with reduced SC abundance, extracellular matrix abnormalities and reduced serial sarcomere number resulting in greatly increased in vivo sarcomere length, perhaps due to impaired sarcomere addition, compared to children with typical development (TD). Stretch is a strong activator of SCs that leads to addition of sarcomeres during bone-muscle growth. Mechanical loading and subsequent deformation of intracellular structures can lead to activation and proliferation, perhaps by cytoskeletal transmissions of extracellular mechanical signals to the nuclei. The primary aim of this study was to determine the effect of ex vivo stretch-induced sarcomere length change on SC deformation in children with CP and TD. Muscle biopsies were obtained from twelve children (7 CP, 5 TD) during surgery. Fiber bundles were labeled with fluorescent antibodies for Pax7 (SC), DRAQ5 (nuclei), and alpha-actinin (sarcomere protein). Fibers were stretched using a custom jig and imaged using confocal microscopy. SC nuclear length, height and aspect ratio underwent increased deformation with increasing sarcomere length (p < 0.05) in both groups. Slopes of association for SC nuclear length, aspect ratio and sarcomere lengths were similar between CP and TD. Our results indicate that SC in children with CP undergo similar deformation as TD across sarcomere lengths., (Published by Elsevier Ltd.)

Skeletal muscle contractile proteins require a constant supply of energy to produce force needed for movement. Energy (ATP) is primarily produced by mitochondrial organelles, located within and around muscle fibers, by oxidative phosphorylation that couples electron flux through the electron transport chain to create a proton gradient across the inner mitochondrial membrane that is in turn used by the ATP synthase. Mitochondrial networks increase in size by biogenesis to increase mitochondrial abundance and activity in response to endurance exercise, while their function and content reduce with constant inactivity, such as during muscle atrophy. During healthy aging, there is an overall decline in mitochondrial activity and abundance, increase in mitochondrial DNA mutations, potential increase in oxidative stress, and reduction in overall muscular capacity. Many of these alterations can be attenuated by consistent endurance exercise. Children with cerebral palsy (CP) have significantly increased energetics of movement, reduced endurance capacity, and increased perceived effort. Recent work in leg muscles in ambulatory children with CP show a marked reduction in mitochondrial function. Arm muscles show that mitochondrial protein content and mitochondria DNA copy number are lower, suggesting a reduction in mitochondrial abundance, along with a reduction in markers for mitochondrial biogenesis. Gene expression networks are reduced for glycolytic and mitochondrial pathways and share similarities with gene networks with aging and chronic inactivity. Given the importance of mitochondria for energy production and changes with aging, future work needs to assess changes in mitochondria across the lifespan in people with CP and the effect of exercise on promoting metabolic health., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dayanidhi.)

Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 ( CHCHD10 ) have been identified in patients suffering from various degenerative diseases including mitochondrial myopathy, spinal muscular atrophy Jokela type, frontotemporal dementia, and/or amyotrophic lateral sclerosis (ALS). The pathogenic mechanism underlying CHCHD10 -linked divergent disorders remains largely unknown. Here we show that transgenic mice overexpressing an ALS-linked CHCHD10 p.R15L mutation leads to an abbreviated lifespan compared with CHCHD10-WT transgenic mice. The occurrence and severity of the phenotype correlates to transgene copy number. Central nervous system (CNS), skeletal muscle, and cardiac pathology is apparent in CHCHD10-R15L transgenic mice. Despite the pathology, CHCHD10-R15L transgenic mice perform comparably to control mice in motor behavioral tasks until very close to death. Although paralysis is not observed, these models provide insight into the pleiotropic nature of CHCHD10 and suggest a contribution of CNS, skeletal muscle, and cardiac pathology to CHCHD10 p.R15L-ALS pathogenesis., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Limb contractures are debilitating complications associated with various muscle and nervous system disorders. This report summarizes presentations at a conference at the Shirley Ryan AbilityLab in Chicago, Illinois, on April 19-20, 2018, involving researchers and physicians from diverse disciplines who convened to discuss current clinical and preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, cerebral palsy, and other conditions. Presenters described changes in muscle architecture, activation, extracellular matrix, satellite cells, and muscle fiber sarcomeric structure that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint, and neuronal tissues during contracture development with imaging, molecular, and physiologic approaches. Participants identified the requirement for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development., (© 2020 Wiley Periodicals, Inc.)

Background: Children with cerebral palsy have impaired muscle growth and muscular contractures that limit their ROM. Contractures have a decreased number of serial sarcomeres and overstretched lengths, suggesting an association with a reduced ability to add the serial sarcomeres required for normal postnatal growth. Contractures also show a markedly reduced number of satellite cells-the muscle stem cells that are indispensable for postnatal muscle growth, repair, and regeneration. The potential role of the reduced number of muscle stem cells in impaired sarcomere addition leading to contractures must be evaluated., Questions/purposes: (1) Does a reduced satellite cell number impair the addition of serial sarcomeres during recovery from an immobilization-induced contracture? (2) Is the severity of contracture due to the decreased number of serial sarcomeres or increased collagen content?, Methods: The hindlimbs of satellite cell-specific Cre-inducible mice (Pax7; Rosa26; n = 10) were maintained in plantarflexion with plaster casts for 2 weeks so that the soleus was chronically shortened and the number of its serial sarcomeres was reduced by approximately 20%. Subsequently, mice were treated with either tamoxifen to reduce the number of satellite cells or a vehicle (an injection and handling control). The transgenic mouse model with satellite cell ablation combined with a casting model to reduce serial sarcomere number recreates two features observed in muscular contractures in children with cerebral palsy. After 30 days, the casts were removed, the mice ankles were in plantarflexion, and the mice's ability to recover its ankle ROM by cage remobilization for 30 days were evaluated. We quantified the number of serial sarcomeres, myofiber area, and collagen content of the soleus muscle as well as maximal ankle dorsiflexion at the end of the recovery period., Results: Mice with reduced satellite cell numbers did not regain normal ankle ROM in dorsiflexion; that is, the muscles remained in plantarflexion contracture (-16° ± 13° versus 31° ± 39° for the control group, -47 [95% confidence interval -89 to -5]; p = 0.03). Serial sarcomere number of the soleus was lower on the casted side than the contralateral side of the mice with a reduced number of satellite cells (2214 ± 333 versus 2543 ± 206, -329 [95% CI -650 to -9]; p = 0.04) but not different in the control group (2644 ± 194 versus 2729 ± 249, -85 [95% CI -406 to 236]; p = 0.97). The degree of contracture was strongly associated with the number of sarcomeres and myofiber area (r =0.80; P < 0.01) rather than collagen content. No differences were seen between groups in terms of collagen content and the fraction of muscle area., Conclusions: We found that a reduced number of muscle stem cells in a transgenic mouse model impaired the muscle's ability to add sarcomeres in series and thus to recover from an immobilization-induced contracture., Clinical Relevance: The results of our study in transgenic mouse muscle suggests there may be a mechanistic relationship between a reduced number of satellite cells and a reduced number of serial sarcomeres. Contracture development, secondary to impaired sarcomere addition in muscles in children with cerebral palsy may be due to a reduced number of muscle stem cells.

Introduction: Muscles add sarcomeres in response to stretch, presumably to maintain optimal sarcomere length. Clinical evidence from patients with cerebral palsy, who have both decreased serial sarcomere number and reduced satellite cells (SCs), suggests a hypothesis that SCs may be involved in sarcomere addition., Methods: A transgenic Pax7-DTA mouse model underwent conditional SC depletion, and their soleii were then stretch-immobilized to assess the capacity for sarcomere addition. Muscle architecture, morphology, and extracellular matrix (ECM) changes were also evaluated., Results: Mice in the SC-reduced group achieved normal serial sarcomere addition in response to stretch. However, muscle fiber cross-sectional area was significantly smaller and was associated with hypertrophic ECM changes, consistent with fibrosis., Conclusions: While a reduced SC population does not hinder serial sarcomere addition, SCs play a role in muscle adaptation to chronic stretch that involves maintenance of both fiber cross-sectional area and ECM structure. Muscle Nerve 55: 384-392, 2017., Competing Interests: None of the authors have any conflict of interest or financial disclosures related to this work., (© 2016 Wiley Periodicals, Inc.)

Introduction: Children with cerebral palsy (CP) exhibit increased energy expenditure during movement, but whether this is due in part to decrements in skeletal muscle mitochondrial oxidative capacity is unknown. Accordingly, we compared fiber-type specific succinate dehydrogenase (SDH) activity in children with CP with typically developing (TD) children., Methods: SDH activity and myofiber areas of type 1 and 2A fibers were measured in semitendinosus biopsies of both groups (n = 5/group)., Results: SDH activity was ∼35% higher in type 1 compared with type 2A fibers, but there were no differences between groups. Average myofiber area was 45% smaller in CP versus TD (P < 0.05), and type 2A fibers were 32% larger than type 1 fibers (P < 0.05) only in TD children., Conclusions: Fiber-type specific SDH activity is similar between TD children and children with CP. This suggests that increased energy expenditure in children with CP is not related to impaired mitochondrial oxidative capacity. Muscle Nerve, 2016 Muscle Nerve 55: 122-124, 2017., (© 2016 Wiley Periodicals, Inc.)

Synopsis It is generally accepted that up to 50% of those with a whiplash injury following a motor vehicle collision will fail to fully recover. Twenty-five percent of these patients will demonstrate a markedly complex clinical picture that includes severe pain-related disability, sensory and motor disturbances, and psychological distress. A number of psychosocial factors have shown prognostic value for recovery following whiplash from a motor vehicle collision. To date, no management approach (eg, physical therapies, education, psychological interventions, or interdisciplinary strategies) for acute whiplash has positively influenced recovery rates. For many of the probable pathoanatomical lesions (eg, fracture, ligamentous rupture, disc injury), there remains a lack of available clinical tests for identifying their presence. Fractures, particularly at the craniovertebral and cervicothoracic junctions, may be radiographically occult. While high-resolution computed tomography scans can detect fractures, there remains a lack of prevalence data for fractures in this population. Conventional magnetic resonance imaging has not consistently revealed lesions in patients with acute or chronic whiplash, a "failure" that may be due to limitations in the resolution of available devices and the use of standard sequences. The technological evolution of imaging techniques and sequences eventually might provide greater resolution to reveal currently elusive anatomical lesions (or, perhaps more importantly, temporal changes in physiological responses to assumed lesions) in those patients at risk of poor recovery. Preliminary findings from 2 prospective cohort studies in 2 different countries suggest that this is so, as evidenced by changes to the structure of skeletal muscles in those who do not fully recover. In this clinical commentary, we will briefly introduce the available imaging decision rules and the current knowledge underlying the pathomechanics and pathophysiology of whiplash. We will then acknowledge known prognostic factors underlying functional recovery. Last, we will highlight emerging evidence regarding the pathobiology of muscle degeneration/regeneration, as well as advancements in neuroimaging and musculoskeletal imaging techniques (eg, functional magnetic resonance imaging, magnetization transfer imaging, spectroscopy, diffusion-weighted imaging) that may be used as noninvasive and objective complements to known prognostic factors associated with whiplash recovery, in particular, poor functional recovery. J Orthop Sports Phys Ther 2016;46(10):861-872. doi:10.2519/jospt.2016.6735.

Satellite cells (SC) are quiescent adult muscle stem cells critical for postnatal development. Children with cerebral palsy have impaired muscular growth and develop contractures. While flow cytometry previously demonstrated a reduced SC population, extracellular matrix abnormalities may influence the cell isolation methods used, systematically isolating fewer cells from CP muscle and creating a biased result. Consequently, the purpose of this study was to use immunohistochemistry on serial muscle sections to quantify SC in situ. Serial cross-sections from human gracilis muscle biopsies (n = 11) were labeled with fluorescent antibodies for Pax7 (SC transcriptional marker), laminin (basal lamina), and 4',6-diamidino-2-phenylindole (nuclei). Fluorescence microscopy under high magnification was used to identify SC based on labeling and location. Mean SC/100 myofibers was reduced by ∼70% (p < 0.001) in children with CP (2.89 ± 0.39) compared to TD children (8.77 ± 0.79). Furthermore, SC distribution across fields was different (p < 0.05) with increased percentage of SC in fields being solitary cells (p < 0.01) in children with CP. Quantification of SC number in situ, without any other tissue manipulation confirms children with spastic CP have a reduced number. This stem cell loss may, in part, explain impaired muscle growth and apparent decreased responsiveness of CP muscle to exercise., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Understanding the mapping between individual outcome measures and the latent functional domains of interest is critical to a quantitative evaluation and rehabilitation of hand function. We examined whether and how the associations among six hand-specific outcome measures reveal latent functional domains in elderly individuals. We asked 66 healthy older adult participants (38F, 28M, 66.1 ± 11.6 years, range: 45-88 years) and 33 older adults (65.8 ± 9.7 years, 44-81 years, 51 hands) diagnosed with osteoarthritis (OA) of the carpometacarpal (CMC) joint, to complete six functional assessments: hand strength (Grip, Key and Precision Pinch), Box and Block, Nine Hole Pegboard, and Strength-Dexterity tests. The first three principal components suffice to explain 86% of variance among the six outcome measures in healthy older adults, and 84% of variance in older adults with CMC OA. The composition of these dominant associations revealed three distinct latent functional domains: strength, coordinated upper extremity function, and sensorimotor processing. Furthermore, in participants with thumb CMC OA we found a blurring of the associations between the latent functional domains of strength and coordinated upper extremity function. This motivates future work to understand how the physiological effects of thumb CMC OA lead upper extremity coordination to become strongly associated with strength, while dynamic sensorimotor ability remains an independent functional domain. Thus, when assessing the level of hand function in our growing older adult populations, it is particularly important to acknowledge its multidimensional nature-and explicitly consider how each outcome measure maps to these three latent and fundamental domains of function. Moreover, this ability to distinguish among latent functional domains may facilitate the design of treatment modalities to target the rehabilitation of each of them.

Study Design: Retrospective Cohort, Introduction: Important outcomes of polliciation to treat thumb hypoplasia/aplasia include strength, function, dexterity, and quality of life., Purpose of the Study: To evaluate outcomes and examine predictors of outcome after early childhood pollicization., Methods: 8 children (10 hands) were evaluated 3-15 years after surgery. Physical examination, questionnaires, grip and pinch strength, Box and Blocks, 9-hole pegboard, and strength-dexterity (S-D) tests were performed., Results: Pollicized hands had poor strength and performance on functional tests. Six of 10 pollicized hands had normal dexterity scores but less stability in maintaining a steady-state force. Predictors of poorer outcomes included older age at surgery, reduced metacarpophalangeal and interphalangeal range of motion, and radial absence., Discussion: Pollicization resulted in poor strength and overall function, but normal dexterity was often achieved using altered control strategies., Conclusions: Most children should obtain adequate dexterity despite weakness after pollicization except older or severely involved children., Level of Evidence: IV., (Copyright © 2015 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.)

The corticospinal and the rubrospinal tracts are thought to synergistically contribute to the limb control during motor development. Williams et al. (J Neurosci 34: 4432-4441, 2014) demonstrate that the postnatal maturation of red nucleus motor map and the rubrospinal tract develops earlier than the corticospinal tract, to support early forelimb control. They have two distinct phases of maturation; a "precorticospinal" phase characterized by development of the rubrospinal system, and a "cocorticospinal" phase where they overlap with corticospinal development.

Dexterity after finger pollicization (reconstruction to thumb) is critical to functional outcomes. While most tests of hand function evaluate a combination of strength, coordination, and motor control, the Strength-Dexterity (S-D) paradigm focuses on the dynamic control of fingertip forces. We evaluated 10 pollicized and 5 non-pollicized hands from 8 participants ages 4-17 years (2 female, 6 male; 10.6 ± 4.5 years). Participants partially compressed and held an instrumented spring prone to buckling between the thumb and first finger to quantify dynamic control over the direction and magnitude of fingertip forces. They also completed traditional functional tests including grip, lateral pinch, and tripod pinch strength, Box and Blocks, and 9-hole peg test. Six of 10 pollicized hands and all non-pollicized hands had S-D scores comparable to typically developing children. However, dynamical analysis showed that pollicized hands exhibit greater variability in compression force, indicating poorer corrective action. Almost all pollicized hands scored below the normal range for the traditional functional tests. The S-D test Z-scores correlated moderately with Z-scores from the other functional tests (r = 0.54-0.61; p = 0.02-0.04) but more weakly than amongst the other functional measures (r = 0.58-0.83; p = 0.0002-0.02), suggesting that the S-D test captures a different domain of function. A higher incidence of radial absence in the hands with poor S-D scores (3/4 vs. 0/6 in hands with normal S-D scores, p = 0.03) was the only clinical characteristic associated with S-D outcome. Overall, these results suggest that while most pollicized hands can control fingertip forces, the nature of that control is altered., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Satellite cells (SCs) are the muscle stem cells responsible for longitudinal and cross-sectional postnatal growth and repair after injury and which provide new myonuclei when needed. We review their morphology and contribution to development and their role in sarcomere and myonuclear addition. SCs, similar to other tissue stem cells, cycle through different states, such as quiescence, activation, and self-renewal, and thus we consider the signaling mechanisms involved in maintenance of these states. The role of the SC niche and their interactions with other cells, such as fibroblasts and the extracellular matrix, are all emerging as major factors that affect aging and disease. Interestingly, children with cerebral palsy appear to have a reduced SC number, which could play a role in their reduced muscular development and even in muscular contracture formation. Finally, we review the current information on SC dysfunction in children with muscular dystrophy and emerging therapies that target promotion of myogenesis and reduction of fibrosis., (© 2014 Wiley Periodicals, Inc.)

Raman spectroscopy (RS) has been extensively used to characterize bone composition. However, the link between bone biomechanics and RS measures is not well established. Here, we leveraged the sensitivity of RS polarization to organization, thereby assessing whether RS can explain differences in bone toughness in genetic mouse models for which traditional RS peak ratios are not informative. In the selected mutant mice—activating transcription factor 4 (ATF4) or matrix metalloproteinase 9 (MMP9) knock-outs—toughness is reduced but differences in bone strength do not exist between knock-out and corresponding wild-type controls. To incorporate differences in the RS of bone occurring at peak shoulders, a multivariate approach was used. Full spectrum principal components analysis of two paired, orthogonal bone orientations (relative to laser polarization) improved genotype classification and correlation to bone toughness when compared to traditional peak ratios. When applied to femurs from wild-type mice at 8 and 20 weeks of age, the principal components of orthogonal bone orientations improved age classification but not the explanation of the maturation-related increase in strength. Overall, increasing polarization information by collecting spectra from two bone orientations improves the ability of multivariate RS to explain variance in bone toughness, likely due to polarization sensitivity to organizational changes in both mineral and collagen.

Background: The ability to dynamically control fingertip force vector magnitude and direction is critical for dexterous manipulation. We quantified the dynamic control of fingertip forces to examine how dexterous manipulation declines with age., Methods: The strength-dexterity (SD) test measures fingertip forces during compression of a slender spring prone to instability and buckling. The greatest sustained compression (designed to be under 3 N), and force dynamics therein, have been shown to be simple and quick measures of dynamic dexterous manipulation ability. We measured pinch strength and strength-dexterity test in a cross-sectional population of 98 people from 18 to 89 years of age., Results: Dexterous manipulation ability is poorer at older ages, beginning in middle age (p < .001), with greater decline past 65 years of age. Fingertip force dynamics during spring compression and stabilization show a deterioration of neuromuscular control with age. Importantly, this novel detection of decline in dynamic manipulation ability is not correlated with, and thus cannot be entirely explained by, the known decline in pinch strength. We also measured standardized tests of dexterity in participants older than 45, and discuss how the strength-dexterity test uniquely captures features of sensorimotor capabilities for dexterous manipulation in this adult population., Conclusions: Starting in middle age, changes in the functional interactions among sensory, motor, and neural capabilities result in measurably poorer dynamic dexterous manipulation. This deterioration of neuromuscular control motivates and enables future studies to understand the physiological bases for this functional decline so critical to activities of daily living and quality of life., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While it is clear that the development of dexterous manipulation in children exhibits dramatic improvements over an extended period, it is difficult to separate musculoskeletal from neural contributors to these important functional gains. This is in part due to the inability of current methods to disambiguate improvements in hand strength from gains in finger dexterity (i.e., the dynamic control of fingertip force vectors at low magnitudes). We adapted our novel instrumentation to evaluate finger dexterity in 130 typically developing children between the ages of 4 and 16 yr. We find that finger dexterity continues to develop well into late adolescence and musculoskeletal growth and strength are poorly correlated with the improvements in dexterity. Importantly, because these behavioral results seem to mirror the known timelines of neuroanatomical development up to adolescence, we speculate that they reflect the functional benefits of such continual neural maturation. This novel perspective now enables the systematic study of the functional roles of specific neuroanatomical structures and their connectivity, maturity, and plasticity. Moreover, the temporal dynamics of the fingertip force vectors shows improvements in stability that provide a novel way to look at the maturation of finger control. From a clinical perspective, our results provide a practical means to chart functional development of dexterous manipulation in typically developing children and could be adapted for clinical use and for use in children with developmental disorders.

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

Background: Shoulder movement patterns differ between limbs of children with unilateral brachial plexus birth palsy. To better understand the interlimb differences we examined the glenohumeral and scapulothoracic joint contributions to arm elevation., Methods: Sixteen children with brachial plexus birth palsy, 4-12 years of age participated. Shoulder 3D kinematic data were collected using a magnetic tracking device during arm elevation with the involved and non-involved limbs for three trials each at a fixed rate. Based on maximum arm elevation in the involved limb the children were divided into two groups: group one 75 degrees ., Findings: During arm elevation from 15 to 75 degrees the involved limb of group one displayed lower glenohumeral joint excursion than the non-involved and both limbs of group two. Scapular upward rotation was higher in the involved limb of both groups. For group one, the glenohumeral:scapulothoracic ratio for 15-75 degrees arm elevation was lower in the involved (0.6:1) than the non-involved (2.2:1) limb and both limbs of group two: involved (1.7:1); non-involved (1.9:1). During 15-135 degrees arm elevation for group two, the glenohumeral:scapulothoracic ratio was more similar between limbs: involved (1.5:1) and non-involved (2:1)., Interpretation: The scapulothoracic joint made a greater contribution to arm elevation than the glenohumeral joint only in the involved limb of group one, altering the scapulohumeral rhythm. Musculoskeletal and neural factors may account for the group and limb differences. Routine 3D kinematic analysis of shoulder joint rotation may aid treatment planning and better quantify outcomes in this group.

Background: Appropriate motion of the scapula is important for dynamic positioning of the glenoid during humeral elevation. A number of studies have described the typical scapular kinematics during humeral elevation in adults. However, children and adults may have differences in scapulothoracic musculature and scapular osteology. To our knowledge, no study has been performed examining scapular kinematics in children with either typical or atypical development. Consequently in children the influence of age and development on scapular motion is currently unknown. The aim of this study was to describe and compare the kinematic patterns of the scapula during humeral elevation in children with typical development and healthy adults., Methods: Fifteen adults, 7 females, 25-37 years of age, and 14 children, 8 females, 4-9 years of age, participated in this study. Kinematic data were collected using a magnetic tracking device. Subjects were asked to elevate their arm in the scapular plane (40 degrees anterior to the frontal plane) in a sequence of three trials., Findings: Significant differences were seen between the two age groups in the dependent variables. During scapular plane rotation from 25 degrees to 125 degrees , children showed greater upward rotation (43.9 degrees SD 6.39 degrees ) than adults (29.1 degrees SD 10.1 degrees ). The mean glenohumeral to scapulothoracic ratio in the scapular plane was 2.4:1 for adults, 1.3:1 for children., Interpretation: This study demonstrates that there are significant differences in scapular kinematic patterns between children and adults. Children have a greater contribution from the scapulothoracic joint, specifically upward rotation toward humeral elevation. From a clinical perspective, these results can be used to help determine the incorporation of stabilization and mobilization of the scapulothoracic joint during exercises for a child with impairment at the shoulder for improving shoulder function.