Flexor Digitorum Brevis Research Articles

Effects of Toe Tube Training on Intrinsic Foot Muscle Strength and Reactive Strength Index in Runners: A Randomized Controlled Trial

Long-distance runners are known to be at a high risk of lower limb disorders due to a decline in the function of the intrinsic foot muscles (IFMs). The aim of this study was to examine the effects of toe tube training using elastic tubes. First, a crossover study was conducted with 13 healthy adults in three conditions: tube training, short foot exercise, and control. Changes in the IFMs pre- and post-exercise were confirmed using ultrasound echo. Next, 19 university long-distance runners were randomly divided into two groups (tube training or short foot exercise) and underwent a five-week training intervention. The toe grip strength, toe gap strength, and reactive strength index were measured pre- and post-intervention. In a crossover study, the tube training and short foot exercise showed a significant interaction effect on the abductor hallucis brevis (F = 5.63, p = 0.010, partial η2 = 0.32) and flexor digitorum brevis (F = 15.29, p < 0.001, partial η2 = 0.56), confirming an immediate effect of tube training and short foot exercise. In an intervention study with runners, no interaction was observed but a main effect of time was found, with both groups showing significant improvements in toe grip strength (F = 25.64, p < 0.001, partial η2 = 0.60), toe gap strength (F = 11.26, p = 0.004, partial η2 = 0.40), and RSI (F = 4.81, p = 0.042, partial η2 = 0.22). Tube training may be an effective alternative for runners who find short foot exercise difficult and want to adjust the exercise load.

Novel voltage-dependent Cl− channels in striatal medium spiny neurons are unrelated to ClC-1 or other known Ca2+-induced Cl− channel/transporter types

Intracellular chloride (Cl−) homeostasis is a critical regulator of neuronal excitability. Voltage-dependent neuronal Cl− channels remain the least understood in terms of their role as a source of Cl− entry controlling excitability. We have shown recently that striatal medium spiny neurons (MSNs) express a functional Cl− conducting ClC-1-like channel with properties similar but not identical to native ClC-1 channels (Yarotskyy, V., Lark, A.R.S., Nass S.R., Hahn, Y.K., Marone, M.G., McQuiston, A.R., Knapp, P.E., Hauser, K.F. (2022) Am. J. Physiol. Cell. Physiol. 322 (2022) C395-C409). Using a myotonic SWR/J-Clcn1adr-mto/J mouse model with a premature stop codon for the ClC-1 channel rendering it non-functional, we demonstrate that striatal MSNs isolated from wild type (wt) and homozygous mutant (adr) mouse embryos have identical voltage-dependent outwardly rectifying Cl− currents. In contrast and as expected, homozygous adr skeletal muscle flexor digitorum brevis (FDB) fibers display nominal macroscopic Cl− currents compared to heterozygous wild-type adr FDB fibers. Together, our findings demonstrate that the novel ClC-1-like channels in MSNs are unrelated to skeletal muscle-specific ClC-1 channels, and therefore represent a unique voltage-dependent neuronal Cl− channel of unknown identity.

Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.

Cancer cachexia, and the related loss of muscle and strength, worsens quality of life and lowers overall survival. Recently, a novel 'pre-atrophy' muscle weakness was identified during early-stage cancer. While mitochondrial stress responses are associated with early-stage pre-atrophy weakness, a causal relationship has not been established. Using a robust mouse model of metastatic epithelial ovarian cancer (EOC)-induced cachexia, we found the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents pre-atrophy weakness in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. EOC reduced flexor digitorum brevis (FDB) force production and myoplasmic free calcium ([Ca 2+ ] i ) during contraction in single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout EOC. These discoveries identify that muscle weakness can occur independent of atrophy throughout EOC in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force during the early pre-atrophy period and in late-stage EOC once cachexia has become severe.

Glucose and glycogen affects Ca2+ transient during fatigue to a greater extent in the least than in the most fatigue resistant mouse FDB fibers.

The overall objective was to determine how no extracellular glucose and/or low glycogen content affect fatigue kinetics in mouse flexor digitorum brevis (FDB) single muscle fibers. High glycogen content (Hi GLY), near normal insitu level, was obtained by incubating fibers in culture medium containing glucose and insulin while low glycogen content (Lo GLY), at about 19% of normal insitu level, was achieved by incubating fibers without glucose. Neither Lo GLY nor the absence of extracellular glucose (0GLU) affected tetanic [Ca2+]i prior to fatigue. The number of contracting unfatigued fibers versus stimulus strength relationship of Lo GLY-0GLU fibers was shifted to higher voltages compared to Hi GLY fibers exposed to 5.5 mM glucose (5GLU). The relationship for Lo GLY-0GLU fibers was shifted back toward that of Hi GLY-5GLU fibers when glucose was reintroduced, whereas the removal of glucose from Hi GLY-5GLU fibers had no effect. Fatigue was elicited with one 200 ms long tetanic contraction every s for 3 min. Both Lo GLY and 0GLU increased the rate at which intracellular tetanic concentration ([Ca2+]i) declined and unstimulated [Ca2+]i increased during fatigue in the order of the least fatigue resistant > mid fatigue resistant > the most fatigue resistant fibers.

Mechanical drivers of intrinsic foot muscle for maximum toe flexor strength in upright standing across different body size

This study aimed to evaluate maximum toe flexor strength, foot arch height, intrinsic toe flexor muscle size and foot arch stiffness among individuals with different body sizes, and to compare these variables between sitting and standing positions. Maximum toe flexor strength in sitting and standing, and intrinsic foot muscle thicknesses (flexor hallucis brevis: FHB, flexor digitorum brevis: FDB, abductor hallucis: AH and quadratus plantae: QP), were measured using a toe grip dynamometer and a B-mode ultrasound in healthy young men. FHB was thicker than AH, FDB and QP, AH was thicker than FDB and QP, and no significant difference was found between FDB and QP. Toe flexor strength was correlated with FHB and AH, and foot arch height was correlated with FHB. Toe flexor strength was greater in standing than in sitting. Stepwise multiple regression analysis identified FHB and AH as determinants of toe flexor strength in standing, and the relative muscle strength values per body weight in standing were determined by QP, foot arch index and foot arch stiffness. Overweight individuals had a decreased rate of increase in relative toe flexor strength compared to normal individuals. These results suggest that a large muscle thickness of intrinsic foot muscle a key contributor to toe flexor strength. Moreover, toe flexor muscle in upright standing could have the potential to generate force independently of intrinsic foot muscle size, but obese individuals who chronically put weight on their feet might impair the force amplification mechanism in upright standing.

Differences in the Size of Individual Plantar Intrinsic Foot Muscles Between Ballet Dancers and Non-Dancers.

In classic ballet, choreography often involves tiptoe standing. Tiptoe standing requires a high and stable foot arch structure, which is achieved by contraction of the plantar intrinsic foot muscles (PIFMs). Long-term repetitive loading with a specific movement can induce hypertrophic adaptation of the associated muscles. For dancers, however, limited information on the size of individual PIFMs is available from previous studies. The purpose of this study was to determine the differences in the sizes of 10 individual PIFMs between dancers and non-dancers. Muscle volumes (MVs) of 10 individual PIFMs were measured using magnetic resonance imaging in 15 female dancers and 15 female non-dancers. Muscles analyzed included abductor hallucis, flexor digitorum brevis, abductor digiti minimi, quadratus plantae, lumbricals, flexor hallucis brevis, adductor hallucis oblique head, adductor hallucis transverse head, flexor digiti minimi, plantar/dorsal interossei. In addition to absolute MVs, relative MVs normalized to body mass (rMVBM) and the percentage of individual MVs relative to the sum of 10 individual PIFM MVs (%MVWHOLE) were calculated. The absolute MVs of 6 individual PIFMs, including the flexor digitorum brevis and lumbricals, were +16% to 59% larger in dancers than in non-dancers (P ≤ .048). The rMVBM of all individual PIFMs were +35% to 95% larger in dancers than in non-dancers (P ≤ .019). The %MVWHOLE of the flexor digitorum brevis and lumbricals were +10% to 36% higher (P ≤ .014) and those of the abductor digiti minimi and adductor hallucis oblique head were +8% to 11% lower (P ≤ .037) in dancers than in non-dancers. For all 3 MV measures, only the flexor digitorum brevis and lumbricals, which are functionally specialized for flexion of the second to fifth metatarsophalangeal joints, were consistently larger in dancers than in non-dancers. This may be due to long-term repetitive loading on these PIFMs during ballet training involving tiptoe standing.

Loss of Calpain 3 dysregulates store-operated calcium entry and its exercise response in mice.

Limb-Girdle Muscular Dystrophy R1/2A (LGMD R1/2A) is caused by mutations in the CAPN3 gene encoding Calpain 3, a skeletal-muscle specific, Ca2+-dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca2+ homeostasis. Through live-cell Ca2+ measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) in Capn3 deficient (C3KO) and wild-type (WT) mice, we determined whether loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity. Direct Ca2+ influx measurements revealed loss of Capn3 elicits elevated resting SOCE and increased resting cytosolic Ca2+, supported by high incidence of calcium entry units (CEUs) observed by EM. C3KO and WT mice were subjected to a single bout of treadmill running to elicit SOCE. Within 1HR post-treadmill running, C3KO mice exhibited diminished force production in extensor digitorum longus muscles and a greater decay of Ca2+ transients in flexor digitorum brevis muscle fibers during repetitive stimulation. Striking evidence for impaired exercise-induced SOCE activation in C3KO mice included poor colocalization of key SOCE proteins, stromal-interacting molecule 1 (STIM1) and ORAI1, combined with disappearance of CEUs in C3KO muscles. These results demonstrate that Calpain 3 is a key regulator of SOCE in skeletal muscle and identify SOCE dysregulation as a contributing factor to LGMD R1/2A pathology.

Association between Elastic Modulus of Foot Soft Tissues and Gait Characteristics in Young Individuals with Flatfoot.

Flatfoot is a common foot deformity, causing foot pain, osteoarthritis of the midfoot, and even knee and hip dysfunction. The elastic modulus of foot soft tissues and its association with gait biomechanics still remain unclear. For this study, we recruited 20 young individuals with flatfoot and 22 age-matched individuals with normal foot arches. The elastic modulus of foot soft tissues (posterior tibial tendon, flexor digitorum brevis, plantar fascia, heel fat pad) was obtained via ultrasound elastography. Gait data were acquired using an optical motion capture system. The association between elastic modulus and gait data was analyzed via correlation analysis. The elastic modulus of the plantar fascia (PF) in individuals with flatfoot was higher than that in individuals with normal foot arches. There was no significant difference in the elastic modulus of the posterior tibial tendon (PTT), the flexor digitorum brevis (FDB), or the heel fat pad (HFD), or the thickness of the PF, PTT, FDB, and HFD. Individuals with flatfoot showed greater motion of the hip and pelvis in the coronal plane, longer double-support phase time, and greater maximum hip adduction moment during walking. The elastic modulus of the PF in individuals with flatfoot was positively correlated with the maximum hip extension angle (r = 0.352, p = 0.033) and the maximum hip adduction moment (r = 0.429, p = 0.039). The plantar fascia is an important plantar structure in flatfoot. The alteration of the plantar fascia's elastic modulus is likely a significant contributing factor to gait abnormalities in people with flatfoot. More attention should be given to the plantar fascia in the young population with flatfoot.

Appendicular myology of Skorpiovenator bustingorryi: A first attempt to reconstruct pelvic and hindlimb musculature in an abelisaurid theropod.

We present the pelvic and hindlimb musculature of the abelisaurid Skorpiovenator bustingorryi, constituting the most comprehensive muscle reconstruction to date in ceratosaur theropods. Using extant phylogenetic bracket method, we reconstructed 39 muscles that can commonly found in extant archosaurs. Through the identification of bone correlates, we recognized thigh and hindlimb muscles including knee extensors, m. iliofibularis, m. flexor tibialis externus, mm. caudofemorales, mm. puboischiofemorales, and crus muscles important in foot extension and flexion (e.g., m. tibialis anterior, mm. gastrocnemii). Also, autopodial intrinsic muscles were reconstructed whose function involve extension (m. extensor digiti 2-4), flexion (mm. flexor digitorum brevis superficialis), interdigital adduction (m. interosseus dorsalis) and abduction (m. interosseous plantaris, m. abductor 4). Abelisaurids like Skorpiovenator show a deep pre- and postacetabular blade of the ilia and enlarged cnemial crests, which would have helped increasing the moment arm of muscles related to hip flexion and hindlimb extension. Also, pedal muscles related to pronation were probably present but reduced (e.g., m. pronator profundus). Despite some gross differences in the autopodial morphology in extant outgroups (e.g., crocodilian metatarsus and avian tarsometatarsus), the present study allows us to hypothesize several pedal muscles in Skorpiovenator. These muscles would not be arranged in tendinous bundles as in Neornithes, but rather the condition would be similar to that of crocodilians with several layers formed by fleshy bellies on the plantar and dorsal aspects of the metatarsus. The musculature of Skorpiovenator is key for future studies concerning abelisaurid biomechanics, including the integration of functional morphology and ichnological data.

Comparison by ultrasound shear wave elastography of toe flexor muscle contraction during MTP flexion exercise and short-foot exercise.

The intrinsic foot muscles play an important role in medial longitudinal arch support, as well as several extrinsic foot muscles. While various strength training methods specific to intrinsic foot muscles have been conducted, these exercises are associated with certain concerns regarding their effectiveness and difficulty. We developed a new exercise for the intrinsic muscles (MTP flexion exercise). The aim was to compare the shear modulus of the toe flexors as the muscle contraction activity during MTP flexion and short-foot exercises using ultrasound shear wave elastography. Eleven healthy participants were included in this study. The shear modulus of the toe flexor muscles was measured during MTP flexion and short-foot exercises using ultrasound shear wave elastography. The muscle shear modulus was statistically compared between the resting phase, and during the two exercises. The shear modulus during MTP flexion exercise was significantly greater than in the resting phase in the abductor hallucis, flexor hallucis brevis, flexor digitorum brevis, quadratus plantae, and flexor digitorum longus. The flexor digitorum longus showed greater shear modulus during MTP flexion exercise than during short-foot exercise. MTP flexion exercise showed equivalent or greater contraction activity in certain intrinsic and extrinsic foot muscles when compared with short-foot exercise. This exercise is considered one of the training options for strengthening the intrinsic muscles of the foot.

EMG coherence of foot and ankle muscles increases with a postural challenge in men

BackgroundThe functional role of intrinsic foot muscles in the control of standing balance is often overlooked in rehabilitation, partly because the interactions with ankle muscles are poorly understood. Research questionHow does coactivation of Flexor Digitorum Brevis (FDB) and soleus (SOL) vary across standing tasks of increasing difficulty. MethodsPostural sway (Centre of Pressure, CoP) and the electromyographic (EMG) activity of FDB, SOL, Medial Gastrocnemius (MG) and Tibialis Anterior (TA) were measured during bipedal standing, tandem stance, one-legged balance, and standing on toes. Coherence of the rectified EMG signals for SOL and FDB in two bandwidths (0–5 and 10–20 Hz) was calculated as a coactivation index. Results and significanceThe CoP sway and the EMG activity of all muscles was greater (P<0.05) for the three difficult tasks. Significant coherence between the SOL and FDB EMG activity was found in both frequency regions: 0–5 and 10–20 Hz. The coherence integral increased with the difficulty of the postural task, especially in the 10–20 Hz band. The findings underscore the important role of FDB in the control of standing balance across tasks and its coactivation with SOL. Clinical recommendations to improve balance control need to consider the interaction between the plantar flexor and intrinsic-foot muscles.

Minimalist school shoes improve intrinsic foot muscle size, strength, and arch integrity among primary school students

ABSTRACT Minimalist walking shoes have been shown to improve foot muscle size and strength in active adults, but not in our previous study involving children, which could relate to the more structured footwear used in our study. Hence, this study examined the effects of true minimalists on intrinsic foot muscle size and strength, foot arch integrity, and physical function among primary school children. After a baseline assessment, 30 primary school students aged between 9 and 12 were given a pair of minimalist shoes (minimalist index = 92%) as their regular school shoes for two school terms, followed by a re-assessment. Seventeen of the 30 participants in the minimalist group completed the study. Compared to the control group, the minimalist group showed significantly increased cross-sectional area of abductor hallucis (p = 0.047, Cohen’s d = 0.57) and flexor digitorum brevis (p = 0.037, Cohen’s d = 0.80), increased strength of the hallux (p = 0.015, Cohen’s d = 0.76) and lesser toes (p = 0.014, Cohen’s d = 0.66), greater arch height (p = 0.020, Cohen’s d = 0.52) and standing long jump distance (p = 0.001, Cohen’s d = 9.79). The control group exhibited improved standing long jump performance only (p = 0.020, Cohen’s d = 10.70). Minimalist shoes worn daily to school promote intrinsic foot muscle size and strength, and improve foot arch integrity among primary school students.

The Precision and Safety of Ultrasound-Guided versus Palpation-Guided Needle Placement on the Plantar Fascia and Flexor Digitorum Brevis Interface: An Anatomical Study.

Evidence suggests the plantar fascia and its interphase with the flexor digitorum brevis muscle can play a relevant role in plantar heel pain. Needling interventions could offer an appropriate treatment strategy to addressing this interface. We compared the accuracy and safety of ultrasound-guided versus palpation-guided procedures for the proper targeting of the interface between the plantar fascia and the flexor digitorum brevis with a solid needle. A crossover cadaveric study was conducted. Five experienced therapists performed a series of 20 needle insertions each (n = 100 in total, 10 landmark-guided and 10 ultrasound-guided) on 10 anatomical samples. The therapists were instructed to accurately place the needle on the interface between the plantar fascia and the flexor digitorum brevis muscle. The distance of the tip of the needle to the identified target (accuracy), the surrounding sensitive structures targeted (safety), the time needed for the procedure, the number of needle passes, and the needle length outside the skin were assessed. The ultrasound-guided technique was associated with a significantly higher accuracy (p < 0.001) but without differences in safety (p = 0.249) as compared to the palpation-guided procedure. Our results suggest that ultrasound-guided insertion exhibits greater accuracy but not greater safety than palpation-guided insertion when targeting the interface between the plantar fascia and the flexor digitorum brevis.

Unraveling the evolutionary marathon: improved mitochondrial bioenergetics in CMP-Neu5Ac hydroxylase gene deleted (Cmah−/−) mouse skeletal myofibers

Objective: Humans are unique among hominids in that they are endurance athletes. Inactivation of the CMP-Neu5Ac hydroxylase (CMAH) gene, which encodes a hydroxylase converting sialic acid Neu5Ac to Neu5Gc, is thought to contribute to this exceptional capacity for endurance running. Recently, our group demonstrated improved fatigue resistance and preserved intracellular O2, estimated by NAD(P)H levels in contracting mouse Cmah−/− flexor digitorum brevis (FDB) single fibers under low oxygen tension. Hypothesis: Effcient regulation of mitochondrial oxygen consumption contributes to improved skeletal myofiber fatigue resistance in Cmah−/− mice. Methods: The mitochondrial bioenergetic potential of permeabilized FDB and soleus fiber bundles from wild type (WT) and Cmah−/− mice was evaluated using a physiological creatine kinase clamp method and high-resolution respirometer. Experiments were conducted with pyruvate and malate with or without branched chain amino acids (BCAAs) as the substrates. Respiratory chain conductance and maximal respiration were measured. Results: FDB Cmah−/− fibers from male but not female mice revealed an increase conductance above WT fibers independent of substrate (male: genotype, p=0.006, substrate, ns; female: genotype, ns, substrate, ns). Maximal respiration was also increased only in male FDBs fibers and was even greater when BCAAs were included in the respiration media. (male: genotype, p=0.003, substrate, p=0.0007, interaction, p=0.002.; female: genotype, ns, substrate, ns). Soleus Cmah−/− fibers from male and female mice revealed an increase conductance above WT fiber bundles that was also greater in the presence of BCAAs but only for male mice (male: genotype, p=0.003, substrate, p=0.05.; female: genotype, p=0.009, substrate, ns). Maximal respiration was increased only in male Cmah−/− soleus fibers independent of substrate. (male: genotype, p=0.002, substrate, ns.; female: genotype, ns, substrate, ns). Summary: Fibers from both the FDB and soleus of male Cmah−/− mice have a greater capacity for mitochondrial respiration under a metabolically active state that is similar to myofibers stimulated to repeatedly contraction in a hypoxic environment. Conclusion: These data suggest that effcient regulation of mitochondrial respiration utilizing BCAAs as a substrate, particularly in males, could contribute to an elite endurance phenotype. This project was funded through the UC San Diego Academic Senate Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of high intensity interval training on muscle contractile function 8 weeks following chemically-induced ovarian failure

The negative effects of ovariectomy on muscle contractile function have been well-characterized, however, the effects of gradual ovarian failure (i.e., perimenopausal transition into late-stage menopause) on muscle function over the lifespan have received less attention. Furthermore, whether exercise training can mitigate changes in muscle contractile function associated with menopause is unclear. The objective of this study, using a chemically-induced ovarian failure mouse model (4-vinylcyclohexene diepoxide; VCD), was to investigate time-course changes in muscle contractility of sedentary controls and the potential of high intensity interval training to mitigate any deleterious effects of ovarian failure. Starting at 11wks old, mice were injected with 160mg/kg/day of VCD for 15 days. Twenty-eight (VCD-trained: n=10, VCD-sedentary: n=10, control: n=8) CD1 female mice were used in this study, with the VCD-trained group beginning training at the onset of ovarian failure for a total of 8 weeks. Contractile properties of the plantar flexors were assessed using an in-vivo set-up 8 weeks following the onset of ovarian failure. As well, a fatigue task (repeated maximal isometric contractions until torque decreased by 60%) was performed. Recovery was measured immediately after, and up to 10min following task termination. Upon completion of mechanical testing, mice were sacrificed and intact muscle fibres were isolated from the flexor digitorum brevis, and myoplasmic free Ca2+ (tetanic [Ca2+]i) concentrations were measured across stimulation frequencies of 10-200 Hz and throughout 50 tetanic contractions (70Hz) to replicate our fatigue task. There was no difference in pre-fatigue values across groups for peak twitch torque, peak 100Hz torque, RTD, 10:100Hz torque, tetanic [Ca2+]i during low (10Hz) and high Hz (100Hz) stimulation, and all were reduced similarly immediately following the fatigue task. Repetitions to task failure was similar across groups and tetanic [Ca2+]i during repetitive contractions (n=50) was reduced similarly across groups. As well, all groups recovered similarly across these measures. Torque and RTD did not recover fully by 10min for either measure, while 10Hz, 100Hz and 10:100Hz tetanic [Ca2+]i was recovered immediately following the fatigue task. Given 10Hz torque was relatively maintained following the fatigue task, and there was a ~40% decline in 100Hz torque, the 10:100Hz ratio increased throughout recovery — this, combined with the [Ca2+] data indicate that calcium sensitivity and release are unlikely contributors to impaired force production following the fatigue task across groups. The present study aimed to assess the impact of training on muscle contractility using a mouse model of gradual ovarian failure. Unlike other models of ovarian failure, there does not seem to be any impairment in muscular performance at the joint level in our VCD-mice, and they responded similarly across groups in response to repetitive fatiguing contractions and exercise training. Supported by NSERC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prime editing-mediated correction of the leptin receptor in muscle cells of db/db mice.

Genetic diseases can be caused by monogenic diseases, which result from a single gene mutation in the DNA sequence. Many innovative approaches have been developed to cure monogenic genetic diseases, namely by genome editing. A specific type of genomic editing, prime editing, has the potential advantage to edit the human genome without requiring double-strand breaks or donor DNA templates for editing. Additionally, prime editing does not require a precisely positioned protospacer adjacent motif (PAM) sequence, which offers flexible target and more precise genomic editing. Here we detail a novel construction of a prime editing extended guide RNA (pegRNA) to target mutated leptin receptors in B6.BKS(D)-Leprdb/J mice (db/db mice). The pegRNA was then injected into the flexor digitorum brevis (FDB) muscle of db/db mice to demonstrate in vivo efficacy, which resulted in pegRNA mediated base transversion at endogenous base transversion. Genomic DNA sequencing confirmed that prime editing could correct the mutation of leptin receptor gene in db/db mice. Furthermore, prime editing treated skeletal muscle exhibited enhanced leptin receptor signals. Thus, the current study showed in vivo efficacy of prime editing to correct mutant protein and rescue the physiology associated with functional protein.

Influence of toe flexor muscle fatigue on stiffness of the intrinsic foot muscles

BACKGROUND: Assessing intrinsic foot muscles (IFM) is important for understanding their role in loading movements. Additionally, knowledge of the impact of IFM following toe flexor muscle fatigue may aid the teaching of IFM exercises. OBJECTIVE: To examine the influence of toe flexor muscle fatigue on IFM stiffness using ultrasound shear-wave elastography. METHODS: This study included 19 college students. IFM stiffness at 10%, 50%, and 90% body weight was measured using ultrasound-based shear-wave elastography. IFM including the abductor hallucis (AbH), flexor hallucis brevis (FHB), flexor digitorum brevis (FDB), and quadratus plantae (QP) were assessed. The fatigue induction protocol comprised a series of toe flexions at a controlled pace of 40 beats per minute and an amplitude of 75% of the maximum toe flexor strength for a duration of 5 minutes. RESULTS: Muscle stiffness significantly increased with increasing load. Toe flexor muscle fatigue significantly increased the stiffness of the FDB. CONCLUSIONS: IFM stiffness significantly increased with increasing load, and the stiffness of FDB significantly increased in the toe flexor muscle fatigue condition at DLS and SLS loads. The findings of this study will contribute to the study and clinical setting of IFM exercises.

Time course changes in in vivo muscle mechanical function and Ca2+ regulation of force following experimentally induced gradual ovarian failure in mice.

The abrupt cessation of ovarian hormone release is associated with declines in muscle contractile function, yet the impact of gradual ovarian failure on muscle contractility across peri-, early- and late-stage menopause remains unclear. In this study, a 4-vinylcyclohexene diepoxide (VCD)-induced ovarian failure mouse model was used to examine time course changes in muscle mechanical function. Plantar flexors of female mice (VCD: n=10; CON: n=8) were assessed at 40 (early perimenopause), 80 (late perimenopause), 120 (menopause onset) and 176 (late menopause) days post-initial VCD injection. A torque-frequency relationship was established across a range of frequencies (10-200Hz). Isotonic dynamic contractions were elicited against relative loads (10-80% maximal isometric torque) to determine the torque-velocity-power relationship. Mice then performed a fatigue task using intermittent 100Hz isometric contractions until torque dropped by 60%. Recovery of twitch, 10Hz and 100Hz torque were tracked for 10min post-task failure. Additionally, intact muscle fibres from the flexor digitorum brevis underwent a fatigue task (50 repetitions at 70Hz), and 10 and 100Hz tetanic [Ca2+] were monitored for 10min afterward. VCD mice exhibited 16% lower twitch torque than controls across all time points. Apart from twitch torque, 10Hz torque and 10Hz tetanic [Ca2+], where VCD showed greater values relative to pre-fatigue during recovery, no significant differences were observed between control and VCD mice during recovery. These results indicate that gradual ovarian failure has minimal detriments to in vivo muscle mechanical function, with minor alterations observed primarily for low-frequency stimulation during recovery from fatigue.

SERCA1 Overexpression in Skeletal Muscle Attenuates Muscle Atrophy and Improves Motor Function in a Mouse Model of ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of muscle mass and muscle function. Previous work from our lab demonstrated that skeletal muscles from a mouse model of ALS show elevated intracellular calcium (Ca2+) levels and heightened endoplasmic reticulum (ER) stress. To investigate whether overexpression of sarcoplasmic reticulum (SR) Ca2+ ATPase 1 (SERCA1) in skeletal muscle would improve intracellular Ca2+ handling, attenuate ER stress, and improve motor function ALS transgenic mice. B6SJL-Tg (SOD1*G93A)1Gur/J (ALS-Tg) mice were bred with skeletal muscle α-actinin SERCA1 overexpressing mice to generate wild type (WT), SERCA1 overexpression (WT/+SERCA1), ALS-Tg, and SERCA1 overexpressing ALS-Tg (ALS-Tg/+SERCA1) mice. Motor function (grip test) was assessed weekly and skeletal muscles were harvested at 16 weeks of age to evaluate muscle mass, SR-Ca2+ ATPase activity, levels of SERCA1 and ER stress proteins - protein disulfide isomerase (PDI), Grp78/BiP, and C/EBP homologous protein (CHOP). Single muscle fibers were also isolated from the flexor digitorum brevis muscle to assess changes in resting and peak Fura-2 ratios. ALS-Tg/+SERCA1 mice showed improved motor function, delayed onset of disease, and improved muscle mass compared to ALS-Tg. Further, ALS-Tg/+SERCA1 mice returned levels of SERCA1 protein and SR-Ca2+ ATPase activity back to levels in WT mice. Unexpectedly, SERCA-1 overexpression increased levels of the ER stress maker Grp78/BiP in both WT and ALS-Tg mice, while not altering protein levels of PDI or CHOP. Lastly, single muscle fibers from ALS-Tg/+SERCA1 had similar resting but lower peak Fura-2 levels (at 30 Hz and 100 Hz) compared to ALS-Tg mice. These data indicate that SERCA1 overexpression attenuates the progressive loss of muscle mass and maintains motor function in ALS-Tg mice while not lowering resting Ca2+ levels or ER stress.

A case report on the bilateral absence of fourth tendinous slip of the flexor digitorum brevis muscle in the foot: Exploring evolutionary and surgical relevance

The flexor digitorum brevis (FDB) muscle extends across the central region of the sole, positioned deep beneath the plantar aponeurosis. It inserts into the lateral four toes through four slender musculotendinous slips. Functionally, this muscle reinforces the foot arch by facilitating flexion at the interphalangeal and metatarsophalangeal joints of the lateral toes. In clinical contexts, the FDB muscle serves as a musculocutaneous flap in reconstructive surgeries, addressing various foot deformities. Despite its small size, the FDB muscle carries significant evolutionary importance, indicating potential phylogenetic degeneration in humans due to adaptations to diverse lifestyles. The anatomical variation presented in this case report holds importance, as the presence or absence of the FDB muscle can play a crucial role in maintaining arch integrity and holds relevance from a surgical perspective.