Publications by authors named "Richard L Lieber"

181 Publications

Stretch-induced satellite cell deformation incontracturedmuscles in children with cerebral palsy.

J Biomech 2021 Jul 14;126:110635. Epub 2021 Jul 14.

Department of Bioengineering, University of California, San Diego, CA, USA; Department of Orthopaedic Surgery, University of California, San Diego, CA, USA; Department of Orthopaedics, Rady Children's Hospital, San Diego, CA, USA; Shirley Ryan AbilityLab, Chicago, IL, USA; Edward G Hines VA Medical Center, Maywood, IL, USA. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbiomech.2021.110635DOI Listing
July 2021

Measuring and modeling in vivo human gracilis muscle-tendon unit length.

J Biomech 2021 Jun 26;125:110592. Epub 2021 Jun 26.

Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, United States. Electronic address:

Musculoskeletal models rely heavily on the use of an anatomical dataset and clearly defined assumptions to accurately model the subject being studied. Therefore, it is important to understand the limitations of using musculoskeletal models to study individuals. This paper describes a method of measuring in vivo gracilis muscle-tendon unit length and presents a comparison of experimental data versus predictions from four musculoskeletal models in OpenSim. The largest errors occurred when the knee was fully extended. At this position, the absolute average muscle-tendon unit length error was 7% and the absolute average fiber length error was between 15% and 32%. However, the variability of these errors was significant. Manual linear scaling based on an anthropometric database did not capture the variability observed in subjects. The fiber length errors observed are predicted to have a significant impact on muscle force production that may not represent true subject specific force-length relationship of the gracilis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbiomech.2021.110592DOI Listing
June 2021

Biochemical and structural basis of the passive mechanical properties of whole skeletal muscle.

J Physiol 2021 Jun 7. Epub 2021 Jun 7.

Department of Physical Therapy and Rehabilitation Sciences and School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA, USA.

Passive mechanical properties of whole skeletal muscle are not as well understood as active mechanical properties. Both the structural basis for passive mechanical properties and the properties themselves are challenging to determine because it is not clear which structures within skeletal muscle actually bear passive loads and there are not established standards by which to make mechanical measurements. Evidence suggests that titin bears the majority of the passive load within the single muscle cell. However, at larger scales, such as fascicles and muscles, there is emerging evidence that the extracellular matrix bears the major part of the load. Complicating the ability to quantify and compare across size scales, muscles and species, definitions of muscle passive properties such as stress, strain, modulus and stiffness can be made relative to many reference parameters. These uncertainties make a full understanding of whole muscle passive mechanical properties and modelling these properties very difficult. Future studies defining the specific load bearing structures and their composition and organization are required to fully understand passive mechanics of the whole muscle and develop therapies to treat disorders in which passive muscle properties are altered such as muscular dystrophy, traumatic laceration, and contracture due to upper motor neuron lesion as seen in spinal cord injury, stroke and cerebral palsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP280867DOI Listing
June 2021

Systemic transplantation of adult multipotent stem cells prevents articular cartilage degeneration in a mouse model of accelerated ageing.

Immun Ageing 2021 Jun 7;18(1):27. Epub 2021 Jun 7.

Shirley Ryan Abilitylab (Formerly the Rehabilitation Institute of Chicago), 355 E. Erie St, IL, 60611, Chicago, USA.

Background: Osteoarthritis (OA) is one of the most prevalent joint diseases of advanced age and is a leading cause of disability worldwide. Ageing is a major risk factor for the articular cartilage (AC) degeneration that leads to OA, and the age-related decline in regenerative capacity accelerates OA progression. Here we demonstrate that systemic transplantation of a unique population of adult multipotent muscle-derived stem/progenitor cells (MDSPCs), isolated from young wild-type mice, into Zmpste24 mice (a model of Hutchinson-Gilford progeria syndrome, a condition marked by accelerated ageing), prevents ageing-related homeostatic decline of AC.

Results: MDSPC treatment inhibited expression of cartilage-degrading factors such as pro-inflammatory cytokines and extracellular matrix-proteinases, whereas pro-regenerative markers associated with cartilage mechanical support and tensile strength, cartilage resilience, chondrocyte proliferation and differentiation, and cartilage growth, were increased. Notably, MDSPC transplantation also increased the expression level of genes known for their key roles in immunomodulation, autophagy, stress resistance, pro-longevity, and telomere protection. Our findings also indicate that MDSPC transplantation increased proteoglycan content by regulating chondrocyte proliferation.

Conclusions: Together, these findings demonstrate the ability of systemically transplanted young MDSPCs to preserve a healthy homeostasis and promote tissue regeneration at the molecular and tissue level in progeroid AC. These results highlight the therapeutic potential of systemically delivered multipotent adult stem cells to prevent age-associated AC degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12979-021-00239-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183038PMC
June 2021

Systemic Transplantation of Adult Multipotent Stem Cells Functionally Rejuvenates Aged Articular Cartilage.

Aging Dis 2021 Jun 1;12(3):726-731. Epub 2021 Jun 1.

1Shirley Ryan AbilityLab, Chicago, Illinois, USA.

Osteoarthritis (OA) is the most common and debilitating joint disease of advanced age and has no universally effective therapy. Here, we demonstrate that systemic transplantation of adult multipotent muscle-derived stem/progenitor cells (MDSPCs)-isolated from young mice-rejuvenates the knee articular cartilage (AC) of naturally aged mice. This intervention reduced expression of pro-inflammatory cytokines ( and ) and catabolic matrix-degrading proteinases ( and ) in aged cartilage. Treatment with young MDSPCs also increased expression of pro-regenerative ( and ) and prolongevity genes (), including those associated with chondrocyte proliferation and differentiation, cartilage growth, and telomere protection. Indeed, the AC of MDSPC-treated mice exhibited reduced age-related histological pathologies. Importantly, the reduced mobility and arthritis-related gait dysfunctions of aged mice were also ameliorated by this treatment. Together, our findings demonstrate the rejuvenating effects of systemic transplantation of young MDSPCs on aging AC-at the molecular, tissue, and functional levels. This suggests that MDSPCs, or their secreted factors, may represent a novel therapy that can increase mobility and function in aged or OA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14336/AD.2020.1118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139193PMC
June 2021

A Mobility Measure for Inpatient Rehabilitation Using Multigroup, Multidimensional Methods.

J Neurol Phys Ther 2021 04;45(2):101-111

Shirley Ryan AbilityLab, Chicago, Illinois (C.E.D., J.C., A.J.B., S.M.T., A.W.H., R.L.L., J.A.S.); Department of Physical Therapy and Human Movement Sciences, Northwestern University, Feinberg School of Medicine, Chicago, Illinois (S.M.T.); Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Chicago, Illinois (A.W.H., R.L.L., J.A.S.); and Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (R.L.L.).

Background And Purpose: Inpatient rehabilitation facilities (IRFs) report patient functional status to Medicare and other payers using Quality Indicators (QI). While the QI is useful for payment purposes, its measurement properties are limited for monitoring patient progress. A mobility measure based on QI items and additional standardized assessments may enhance clinicians' ability to track patient improvement. Thus, we developed the Mobility Ability Quotient (Mobility AQ) to assess mobility during inpatient rehabilitation.

Methods: For 10 036 IRF inpatients, we extracted assessments from electronic health records, used confirmatory factor analysis to define subdimensions of mobility, and then applied multidimensional item response theory (MIRT) methods to develop a unidimensional construct. Assessments included the QI items and standardized measures of mobility, motor performance, and wheelchair and transfer skills.

Results: Confirmatory factor analysis resulted in good-fitting models (root-mean-square errors of approximation ≤0.08, comparative fit indices, and nonnormed fit indices ≥0.95) for 3 groups defined by anticipated primary mode of locomotion at discharge-walking, wheelchair propulsion, or both. Reestimation as a multigroup, MIRT model yielded scores more sensitive to change compared with QI mobility items (dlast-first = 1.08 vs 0.60 for the QI; dmax-min = 1.16 vs 1.05 for the QI). True score equating analysis demonstrated a higher ceiling and lower floor for the Mobility AQ than the QI.

Discussion And Conclusions: The Mobility AQ demonstrates improved sensitivity over the QI mobility items. This MIRT-based mobility measure describes patient function and progress for patients served by IRFs and has the potential to reduce assessment burden and improve communication regarding patient functional status.Video Abstract available for more insights from authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A341).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NPT.0000000000000354DOI Listing
April 2021

Characterization of Motor-Evoked Responses Obtained with Transcutaneous Electrical Spinal Stimulation from the Lower-Limb Muscles after Stroke.

Brain Sci 2021 Feb 26;11(3). Epub 2021 Feb 26.

Shirley Ryan AbilityLab, Chicago, IL 60611, USA.

An increasing number of studies suggests that a novel neuromodulation technique targeting the spinal circuitry enhances gait rehabilitation, but research on its application to stroke survivors is limited. Therefore, we investigated the characteristics of spinal motor-evoked responses (sMERs) from lower-limb muscles obtained by transcutaneous spinal cord stimulation (tSCS) after stroke compared to age-matched and younger controls without stroke. Thirty participants (ten stroke survivors, ten age-matched controls, and ten younger controls) completed the study. By using tSCS applied between the L1 and L2 vertebral levels, we compared sMER characteristics (resting motor threshold (RMT), slope of the recruitment curve, and latency) of the tibialis anterior (TA) and medial gastrocnemius (MG) muscles among groups. A single pulse of stimulation was delivered in 5 mA increments, increasing from 5 mA to 250 mA or until the subjects reached their maximum tolerance. The stroke group had an increased RMT (27-51%) compared to both age-matched (TA: = 0.032; MG: = 0.005) and younger controls (TA: 0.001; MG: <0.001). For the TA muscle, the paretic side demonstrated a 13% increased latency compared to the non-paretic side in the stroke group ( = 0.010). Age-matched controls also exhibited an increased RMT compared to younger controls (TA: = 0.002; MG: = 0.007), suggesting that altered sMER characteristics present in stroke survivors may result from both stroke and normal aging. This observation may provide implications for altered spinal motor output after stroke and demonstrates the feasibility of using sMER characteristics as an assessment after stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci11030289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996860PMC
February 2021

Muscle-tendon unit in children with cerebral palsy.

Dev Med Child Neurol 2021 Aug 10;63(8):908-913. Epub 2021 Jan 10.

Nuffield Orthopaedic Centre, Headington, Oxford, UK.

Muscle-tendon unit surgery for correction of deformities and movement dysfunction in children with cerebral palsy (CP) is fairly complicated. An understanding of basic muscle-tendon unit properties and their adaptation to both CP and surgery are important to develop advances in this field. In this review, we provide information to therapists, surgeons, and scientists regarding the short- and long-term adaptations of the muscle-tendon unit. Surgical releases, lengthening, and transpositions are discussed, as are some of the tissue, cellular, and molecular adaptations. What this paper adds Muscle strength, tone, and control must be considered in surgical interventions for cerebral palsy (CP). Muscle-tendon unit lengthening causes significant and lasting weakness requiring prolonged rehabilitation. Sarcomere length increases in CP muscle may be one of the underlying causes of muscle weakness. Muscle satellite cells are decreased and epigenetically modified in a way that may limit muscle growth in CP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14807DOI Listing
August 2021

Skeletal muscle maximal mitochondrial activity in ambulatory children with cerebral palsy.

Dev Med Child Neurol 2021 Jan 3. Epub 2021 Jan 3.

Department of Orthopaedic Surgery, University of California, San Diego, CA, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14785DOI Listing
January 2021

The Lumbricals Are Not the Workhorse of Digital Extension and Do Not Relax Their Own Antagonist.

J Hand Surg Am 2021 Mar 13;46(3):232-235. Epub 2020 Dec 13.

Department of Orthopedic Surgery, Division of Hand and Microvascular Surgery, University of California, San Diego, CA. Electronic address:

That the lumbrical muscles are the workhorse of digital extension and that they can relax their own antagonist have been time-honored principles. However, we believe this dogma is incorrect and an oversimplification. We base our assertion on anatomy, innervation, and the notion that muscle architecture is the most important determinant of muscle function. Wang and colleagues proposed the lumbrical to be a sophisticated tension monitoring device. We elaborate on their well-supported thesis, further proposing that the lumbricals also function as a constant tension spring within the closed loop composed of the digital flexors and the extensor mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhsa.2020.10.022DOI Listing
March 2021

Surgical Mobilization of Skeletal Muscles Changes Functional Properties-Implications for Tendon Transfers.

J Hand Surg Am 2021 Apr 24;46(4):341.e1-341.e10. Epub 2020 Nov 24.

Department of Bioengineering, University of California, La Jolla, CA; Department of Orthopaedic Surgery, University of California, La Jolla, CA; Department of Radiology, University of California, La Jolla, CA.

Purpose: Tendon transfer surgery restores function by rerouting working muscle-tendon units to replace the function of injured or paralyzed muscles. This procedure requires mobilizing a donor muscle relative to its surrounding myofascial connections, which improves the muscle's new line of action and increases excursion. However, the biomechanical effect of mobilization on a donor muscle's force-generating function has not been previously studied under in vivo conditions. The purpose of this study was to quantify the effect of surgical mobilization on active and passive biomechanical properties of 3 large rabbit hind limb muscles.

Methods: Myofascial connections were mobilized stepwise from the distal end to the proximal end of muscles (0%, 25%, 50%, and 75% of muscle length) and their active and passive length-tension curves were measured after each degree of mobilization.

Results: Second toe extensor, a short-fibered muscle, exhibited a 30% decline in peak stress and 70% decline in passive stress, whereas extensor digitorum longus, a short-fibered muscle, and tibialis anterior, a long-fibered muscle, both exhibited similar smaller declines in active (about 18%) and passive stress (about 65%).

Conclusions: The results highlight 3 important points: (1) a trade-off exists between increasing muscle mobility and decreasing force-generating capacity; (2) intermuscular force transmission is important, especially in second toe extensor, because it was able to generate 70% of its premobilization active force although most fibers were freed from their native origin; and (3) muscle architecture is not the major influence on mobilization-induced force impairment.

Clinical Relevance: These data demonstrate that surgical mobilization itself alters the passive and active force-generating capacity of skeletal muscles. Thus, surgical mobilization should not be viewed simply as a method to redirect the line of action of a donor muscle because this procedure has an impact on the functional properties of the donor muscle itself.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhsa.2020.09.017DOI Listing
April 2021

Development of a Multidimensional, Multigroup Measure of Self-Care for Inpatient Rehabilitation.

Arch Phys Med Rehabil 2021 01 6;102(1):97-105. Epub 2020 Oct 6.

Shirley Ryan AbilityLab, Chicago, Illinois.

Objective: To develop and evaluate a measure of clinician-observed and patient-performed self-care function for use during inpatient rehabilitation.

Design: Retrospective analysis of self-care assessments collected by therapists using confirmatory factor analysis (CFA) followed by multidimensional item response theory (MIRT).

Setting: Freestanding inpatient rehabilitation hospital in the Midwestern United States.

Participants: Inpatients (N=7719) with stroke, traumatic brain injury, spinal cord injury, neurologic disorders, and musculoskeletal conditions.

Interventions: Not applicable MAIN OUTCOME MEASURES: A total of 19 clinician-selected self-care measures including the FIM and patient-performed, clinician-rated measures of balance, upper extremity function, strength, changing body position, and swallowing. Clinicians completed assessments on admission and at least 1 interim assessment.

Results: CFA was completed for 3 patient groups defined by their highest level of balance (sitting, standing, walking). We reduced the number of items by 47.5% while maintaining acceptable internal consistency; unidimensionality within each item set required development of testlets. A recursive analysis defined a self-care measure with sensitivity (Cohen d =1.13; Cohen d.=0.91) greater than the FIM self-care items (d.=0.94; d .=0.83). The CFA models provided good to acceptable fit (root mean square error of approximations 0.03-0.06). Most patients with admission FIM self-care ratings of total assistance (88%, 297 of 338) made improvements on the MIRT self-care measure that were undetected by the FIM; the FIM detected no change for 26% of these patients (78 of 297). The remaining 74% (219 of 297) improved on the MIRT-based measure an average of 14 days earlier than was detected by the FIM.

Conclusions: This MIRT self-care measure possesses measurement properties that are superior to the FIM, particularly for patients near its floor or ceiling. Methods assure accommodation for multidimensionality and high levels of sensitivity. This self-care measure has the potential to improve monitoring of self-care and manage therapy effectively during inpatient rehabilitation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.apmr.2020.08.021DOI Listing
January 2021

In vivo supraspinatus muscle contractility and architecture in rabbit.

J Appl Physiol (1985) 2020 12 8;129(6):1405-1412. Epub 2020 Oct 8.

Department of Bioengineering, University of California, San Diego, California.

The rotator cuff (RC) muscles are crucial in moving and stabilizing the glenohumeral joint, and tears can be functionally devastating. Chronic fatty and fibrotic muscle changes, which are nonresponsive to surgical tendon repair, are a focus of contemporary research. The rabbit model recapitulates key biological features of human RC tears, but function and physiology are poorly characterized; limited force and stress data are inconsistent with literature norms in other mammalian species. Here, we present an improved method to assess the physiology of the rabbit supraspinatus muscle (SSP), and we report values for healthy SSP architecture and physiology. Using female New Zealand White Rabbits ( = 6) under 2% isoflurane anesthesia, we surgically isolated the SSP and maximum isometric force measured at 4-6 muscle lengths. Architectural analysis was performed, and maximum isometric stress was computed. Whole muscle length-tension curves were generated using architectural measurements to compare experimental physiology to theoretical predictions. Maximum isometric force (80.87 ± 5.58 N) was dramatically greater than previous reports (11.06 and 16.1 N; < 0.05). Architectural measurement of fiber length (34.25 ± 7.18 mm), muscle mass (9.9 ± 0.93 g), pennation angle (23.67 ± 8.32°), and PCSA (2.57 ± 0.20 cm) were consistent with prior literature. Isometric stress (30.5 ± 3.07 N/cm) was greater than previous reports of rabbit SSP (3.10 and 4.51 N/cm), but similar to mammalian skeletal muscles (15.7-30.13 N/cm). Previous studies underestimated peak force by ∼90%, which has profound implications for interpreting physiological changes as a function of disease state. The data that are presented here enable understanding the physiological implications of disease and repair in the RC of the rabbit. We introduce an improved method to assess rabbit supraspinatus muscle physiology. Maximum isometric force measured for the rabbit supraspinatus was dramatically greater than previous reports in the literature. Consequently, the isometric contractile stress reported is almost 10 times greater than previous reports of rabbit supraspinatus, but similar to available literature of other mammalian skeletal muscle. We show that previous reports of peak supraspinatus isometric force were subphysiological by ∼90.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00609.2020DOI Listing
December 2020

Sensor Anchoring Improves the Correlation Between Intramuscular Pressure and Muscle Tension in a Rabbit Model.

Ann Biomed Eng 2021 Feb 1;49(2):912-921. Epub 2020 Oct 1.

Department of Orthopaedic Surgery, University of California San Diego, La Jolla, CA, USA.

Intramuscular pressure (IMP) shows promise for estimating individual muscle tension in vivo. However, previous pressure measurements show high variability during isometric contraction and poor correlation with tension during dynamic contraction. We hypothesized that enhanced sensor anchoring/orientation would improve tension estimation and thus developed a novel pressure sensor with a barbed housing. Sensors were inserted into the tibialis anterior (TA) of New Zealand White rabbits (N = 8) both parallel and perpendicular to the fiber orientation. We measured muscle stress and IMP during both isometric and dynamic contractions. Passive stress showed good agreement for both insertion directions across muscle lengths (ICC > 0.8). Active stress and IMP agreement were good (ICC = 0.87 ± 0.04) for perpendicular insertions but poor (ICC = 0.21 ± 0.22) for parallel insertions across both dynamic contractions and isometric contractions within the muscle's range of motion. These findings support use of IMP measurements to estimate muscle tension across a range of contraction conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10439-020-02633-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083084PMC
February 2021

Vitamin D ameliorates adipose browning in chronic kidney disease cachexia.

Sci Rep 2020 08 25;10(1):14175. Epub 2020 Aug 25.

Pediatric Nephrology, Rady Children's Hospital San Diego, University of California, San Diego, USA.

Patients with chronic kidney disease (CKD) are often 25(OH)D and 1,25(OH)D insufficient. We studied whether vitamin D repletion could correct aberrant adipose tissue and muscle metabolism in a mouse model of CKD-associated cachexia. Intraperitoneal administration of 25(OH)D and 1,25(OH)D (75 μg/kg/day and 60 ng/kg/day respectively for 6 weeks) normalized serum concentrations of 25(OH)D and 1,25(OH)D in CKD mice. Vitamin D repletion stimulated appetite, normalized weight gain, and improved fat and lean mass content in CKD mice. Vitamin D supplementation attenuated expression of key molecules involved in adipose tissue browning and ameliorated expression of thermogenic genes in adipose tissue and skeletal muscle in CKD mice. Furthermore, repletion of vitamin D improved skeletal muscle fiber size and in vivo muscle function, normalized muscle collagen content and attenuated muscle fat infiltration as well as pathogenetic molecular pathways related to muscle mass regulation in CKD mice. RNAseq analysis was performed on the gastrocnemius muscle. Ingenuity Pathway Analysis revealed that the top 12 differentially expressed genes in CKD were correlated with impaired muscle and neuron regeneration, enhanced muscle thermogenesis and fibrosis. Importantly, vitamin D repletion normalized the expression of those 12 genes in CKD mice. Vitamin D repletion may be an effective therapeutic strategy for adipose tissue browning and muscle wasting in CKD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-70190-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447759PMC
August 2020

Inpatient stroke rehabilitation: prediction of clinical outcomes using a machine-learning approach.

J Neuroeng Rehabil 2020 06 10;17(1):71. Epub 2020 Jun 10.

Max Nader Lab for Rehabilitation Technologies and Outcomes Research, Shirley Ryan AbilityLab, 355 E. Erie St., Chicago, IL, 60611, USA.

Background: In clinical practice, therapists often rely on clinical outcome measures to quantify a patient's impairment and function. Predicting a patient's discharge outcome using baseline clinical information may help clinicians design more targeted treatment strategies and better anticipate the patient's assistive needs and discharge care plan. The objective of this study was to develop predictive models for four standardized clinical outcome measures (Functional Independence Measure, Ten-Meter Walk Test, Six-Minute Walk Test, Berg Balance Scale) during inpatient rehabilitation.

Methods: Fifty stroke survivors admitted to a United States inpatient rehabilitation hospital participated in this study. Predictors chosen for the clinical discharge scores included demographics, stroke characteristics, and scores of clinical tests at admission. We used the Pearson product-moment and Spearman's rank correlation coefficients to calculate correlations among clinical outcome measures and predictors, a cross-validated Lasso regression to develop predictive equations for discharge scores of each clinical outcome measure, and a Random Forest based permutation analysis to compare the relative importance of the predictors.

Results: The predictive equations explained 70-77% of the variance in discharge scores and resulted in a normalized error of 13-15% for predicting the outcomes of new patients. The most important predictors were clinical test scores at admission. Additional variables that affected the discharge score of at least one clinical outcome were time from stroke onset to rehabilitation admission, age, sex, body mass index, race, and diagnosis of dysphasia or speech impairment.

Conclusions: The models presented in this study could help clinicians and researchers to predict the discharge scores of clinical outcomes for individuals enrolled in an inpatient stroke rehabilitation program that adheres to U.S. Medicare standards.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12984-020-00704-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288489PMC
June 2020

Intramuscular Anatomy Drives Collagen Content Variation Within and Between Muscles.

Front Physiol 2020 17;11:293. Epub 2020 Apr 17.

Shirley Ryan AbilityLab, Chicago, IL, United States.

The passive load bearing properties of muscle are poorly understood partly due to challenges in identifying the connective tissue structures that bear loads. Prior attempts to correlate passive mechanical properties with collagen content (often expressed as a mass ratio and used as a surrogate for connective tissue quantity within muscle) have not been successful. This is likely a result of not accounting for variability in intramuscular connective tissue throughout a muscle such that a single collagen content value likely does not adequately represent the connective tissue load bearing capacity of a muscle. Therefore, the purpose of this study was to determine how intramuscular connective tissue distribution throughout a muscle impacts measured collagen content. For this analysis, four mouse hindlimb muscles were chosen because of their varying actions and anatomy; rectus femoris, semimembranosus, tibialis anterior, and lateral gastrocnemius. Collagen content throughout each muscle was determined biochemically using an optimized hydroxyproline assay. Dense connective tissue distribution throughout each muscle's length was quantified histologically. We found that collagen content varied widely within and between muscles, from 3.6 ± 0.40 SEM μg/mg wet weight to 15.6 ± 1.58 SEM μg/mg, which is dependent on both the specific location within a muscle and particular muscle studied. Both collagen content and connective tissue structures demonstrated stereotypically patterns with the highest quantity at the proximal and distal ends of the muscles. Additionally, using three independent approaches: (1) linear regression, (2) predictive modeling, and (3) non-linear optimization, we found complementary and corroborating evidence suggesting a causal relationship between a muscle's connective tissue distribution and collagen content. Specifically, we found that muscle collagen content is driven primarily by its dense connective tissue structures due to the extremely high collagen content of connective tissue (227.52-334.69 μg/mg) compared to muscle tissue (1.93-4.03 μg/mg). A consequence of these findings is that a single collagen content measurement does not accurately represent a muscle's complex distribution of connective tissue. Future studies should account for collagen content variations and connective tissue anatomy to establish more accurate relationships between collagen content measurements and whole muscle passive mechanics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.00293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181957PMC
April 2020

Non-linear Scaling of Passive Mechanical Properties in Fibers, Bundles, Fascicles and Whole Rabbit Muscles.

Front Physiol 2020 20;11:211. Epub 2020 Mar 20.

Department of Bioengineering, University of California, San Diego, San Diego, CA, United States.

Defining variations in skeletal muscle passive mechanical properties at different size scales ranging from single muscle fibers to whole muscles is required in order to understand passive muscle function. It is also of interest from a muscle structural point-of-view to identify the source(s) of passive tension that function at each scale. Thus, we measured passive mechanical properties of single fibers, fiber bundles, fascicles, and whole muscles in three architecturally diverse muscles from New Zealand White rabbits ( = 6) subjected to linear deformation. Passive modulus was quantified at sarcomere lengths across the muscle's anatomical range. Titin molecular mass and collagen content were also quantified at each size scale, and whole muscle architectural properties were measured. Passive modulus increased non-linearly from fiber to whole muscle for all three muscles emphasizing extracellular sources of passive tension ( < 0.001), and was different among muscles ( < 0.001), with significant muscle by size-scale interaction, indicating quantitatively different scaling for each muscle ( < 0.001). These findings provide insight into the structural basis of passive tension and suggest that the extracellular matrix (ECM) is the dominant contributor to whole muscle and fascicle passive tension. They also demonstrate that caution should be used when inferring whole muscle properties from reduced muscle size preparations such as muscle biopsies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098999PMC
March 2020

Pragmatic adaptation of implementation research measures for a novel context and multiple professional roles: a factor analysis study.

BMC Health Serv Res 2020 Mar 30;20(1):257. Epub 2020 Mar 30.

Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Although some advances have been made in recent years, the lack of measures remains a major challenge in the field of implementation research. This results in frequent adaptation of implementation measures for different contexts-including different types of respondents or professional roles-than those for which they were originally developed and validated. The psychometric properties of these adapted measures are often not rigorously evaluated or reported. In this study, we examined the internal consistency, factor structure, and structural invariance of four well-validated measures of inner setting factors across four groups of respondents. The items in these measures were adapted as part of an evaluation of a large-scale organizational change in a rehabilitation hospital, which involved transitioning to a new building and a new model of patient care, facilitated by a significant redesign of patient care and research spaces.

Methods: Items were tailored for the context and perspective of different respondent groups and shortened for pragmatism. Confirmatory factor analysis was then used to test study hypotheses related to fit, internal consistency, and invariance across groups.

Results: The survey was administered to approximately 1208 employees; 785 responded (65% response rate) across the roles of clinician, researcher, leader, support staff, or dual clinician and researcher. For each of the four scales, confirmatory factor analysis demonstrated adequate fit that largely replicated the original measure. However, a few items loaded poorly and were removed from the final models. Internal consistencies of the final scales were acceptable. For scales that were administered to multiple professional roles, factor structures were not statistically different across groups, indicating structural invariance.

Conclusions: The four inner setting measures were robust for use in this new context and across the multiple stakeholder groups surveyed. Shortening these measures did not significantly impair their measurement properties; however, as this study was cross sectional, future studies are required to evaluate the predictive validity and test-retest reliability of these measures. The successful use of adapted measures across contexts, across and between respondent groups, and with fewer items is encouraging, given the current emphasis on designing pragmatic implementation measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12913-020-05118-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106795PMC
March 2020

Conference report on contractures in musculoskeletal and neurological conditions.

Muscle Nerve 2020 06 7;61(6):740-744. Epub 2020 Mar 7.

The Shirley Ryan AbilityLab, Chicago, Illinois.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229996PMC
June 2020

Does a Reduced Number of Muscle Stem Cells Impair the Addition of Sarcomeres and Recovery from a Skeletal Muscle Contracture? A Transgenic Mouse Model.

Clin Orthop Relat Res 2020 04;478(4):886-899

S. Dayanidhi, M. C. Kinney, R. L. Lieber, Department of Orthopaedic Surgery, University of California, San Diego, CA, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CORR.0000000000001134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282569PMC
April 2020

Automating sleep stage classification using wireless, wearable sensors.

NPJ Digit Med 2019 20;2:131. Epub 2019 Dec 20.

Max Nader Lab for Rehabilitation Technologies and Outcomes Research, Shirley Ryan AbilityLab, Chicago, IL 60611 USA.

Polysomnography (PSG) is the current gold standard in high-resolution sleep monitoring; however, this method is obtrusive, expensive, and time-consuming. Conversely, commercially available wrist monitors such as ActiWatch can monitor sleep for multiple days and at low cost, but often overestimate sleep and cannot differentiate between sleep stages, such as rapid eye movement (REM) and non-REM. Wireless wearable sensors are a promising alternative for their portability and access to high-resolution data for customizable analytics. We present a multimodal sensor system measuring hand acceleration, electrocardiography, and distal skin temperature that outperforms the ActiWatch, detecting wake and sleep with a recall of 74.4% and 90.0%, respectively, as well as wake, non-REM, and REM with recall of 73.3%, 59.0%, and 56.0%, respectively. This approach will enable clinicians and researchers to more easily, accurately, and inexpensively assess long-term sleep patterns, diagnose sleep disorders, and monitor risk factors for disease in both laboratory and home settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41746-019-0210-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925191PMC
December 2019

Architecture of the Short External Rotator Muscles of the Hip.

BMC Musculoskelet Disord 2019 Dec 20;20(1):611. Epub 2019 Dec 20.

Departments of Orthopaedic Surgery, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0863, USA.

Background: Muscle architecture, or the arrangement of sarcomeres and fibers within muscles, defines functional capacity. There are limited data that provide an understanding of hip short external rotator muscle architecture. The purpose of this study was thus to characterize the architecture of these small hip muscles.

Methods: Eight muscles from 10 independent human cadaver hips were used in this study (n = 80 muscles). Architectural measurements were made on pectineus, piriformis, gemelli, obturators, quadratus femoris, and gluteus minimus. Muscle mass, fiber length, sarcomere length, and pennation angle were used to calculate the normalized muscle fiber length, which defines excursion, and physiological cross-sectional area (PCSA), which defines force-producing capacity.

Results: Gluteus minimus had the largest PCSA (8.29 cm) followed by obturator externus (4.54 cm), whereas superior gemellus had the smallest PCSA (0.68 cm). Fiber lengths clustered into long (pectineus - 10.38 cm and gluteus minimus - 10.30 cm), moderate (obturator internus - 8.77 cm and externus - 8.04 cm), or short (inferior gemellus - 5.64 and superior gemellus - 4.85). There were no significant differences among muscles in pennation angle which were all nearly zero. When the gemelli and obturators were considered as a single functional unit, their collective PCSA (10.00 cm) exceeded that of gluteus minimus as a substantial force-producing group.

Conclusions: The key findings are that these muscles have relatively small individual PCSAs, short fiber lengths, and low pennation angles. The large collective PCSA and short fiber lengths of the gemelli and obturators suggest that they primarily play a stabilizing role rather than a joint rotating role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12891-019-2995-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925491PMC
December 2019

Contribution of extracellular matrix components to the stiffness of skeletal muscle contractures in patients with cerebral palsy.

Connect Tissue Res 2021 May 28;62(3):287-298. Epub 2019 Nov 28.

Shirley Ryan AbilityLab and Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, IL, USA.

: Joint contractures in children with cerebral palsy contain muscle tissue that is mechanically stiffer with higher collagen content than typically developing children. Interestingly, the correlation between collagen content and stiffness is weak. To date, no data are available on collagen types or other extracellular matrix proteins in these muscles, nor any information regarding their function. Thus, our purpose was to measure specific extracellular protein composition in cerebral palsy and typically developing human muscles along with structural aspects of extracellular matrix architecture to determine the extent to which these explain mechanical properties. : Biopsies were collected from children with cerebral palsy undergoing muscle lengthening procedures and typically developing children undergoing anterior cruciate ligament reconstruction. Tissue was prepared for the determination of collagen types I, III, IV, and VI, proteoglycan, biglycan, decorin, hyaluronic acid/uronic acid and collagen crosslinking. : All collagen types increased in cerebral palsy along with pyridinoline crosslinks, total proteoglycan, and uronic acid. In all cases, type I or total collagen and total proteoglycan were positive predictors, while biglycan was a negative predictor of stiffness. Together these parameters accounted for a greater degree of variance within groups than across groups, demonstrating an altered relationship between extracellular matrix and stiffness with cerebral palsy. Further, stereological analysis revealed a significant increase in collagen fibrils organized in cables and an increased volume fraction of fibroblasts in CP muscle. : These data demonstrate a novel adaptation of muscle extracellular matrix in children with cerebral palsy that includes alterations in extracellular matrix protein composition and structure related to mechanical function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03008207.2019.1694011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253322PMC
May 2021

Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis-associated cachexia.

J Cachexia Sarcopenia Muscle 2020 02 13;11(1):120-134. Epub 2019 Nov 13.

Pediatric Nephrology, Rady Children's Hospital-San Diego, University of California, San Diego, San Diego, CA, USA.

Background: Ctns mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns mice are 25(OH)D and 1,25(OH) D insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns mice.

Methods: Twelve-month-old Ctns mice and wild-type controls were treated with 25(OH)D and 1,25(OH) D (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns mice using RNAseq.

Results: Supplementation of 25(OH)D and 1,25(OH) D normalized serum concentration of 25(OH)D and 1,25(OH) D in Ctns mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF-κB pathway) in inguinal white adipose tissue in Ctns mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL-1β, IL-6, and TNF-α as well as an increased gene expression of Murf-2, atrogin-1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns mice. Importantly, repletion of 25(OH)D and 1,25(OH) D normalized the top 20 differentially expressed genes in Ctns mice.

Conclusions: We report the novel findings that correction of 25(OH)D and 1,25(OH) D insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns mice via multiple cellular and molecular mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015252PMC
February 2020

Myopalladin promotes muscle growth through modulation of the serum response factor pathway.

J Cachexia Sarcopenia Muscle 2020 02 24;11(1):169-194. Epub 2019 Oct 24.

Institute of Genetic and Biomedical Research (IRGB), Milan Unit, National Research Council, Milan, Italy.

Background: Myopalladin (MYPN) is a striated muscle-specific, immunoglobulin-containing protein located in the Z-line and I-band of the sarcomere as well as the nucleus. Heterozygous MYPN gene mutations are associated with hypertrophic, dilated, and restrictive cardiomyopathy, and homozygous loss-of-function truncating mutations have recently been identified in patients with cap myopathy, nemaline myopathy, and congenital myopathy with hanging big toe.

Methods: Constitutive MYPN knockout (MKO) mice were generated, and the role of MYPN in skeletal muscle was studied through molecular, cellular, biochemical, structural, biomechanical, and physiological studies in vivo and in vitro.

Results: MKO mice were 13% smaller compared with wild-type controls and exhibited a 48% reduction in myofibre cross-sectional area (CSA) and significantly increased fibre number. Similarly, reduced myotube width was observed in MKO primary myoblast cultures. Biomechanical studies showed reduced isometric force and power output in MKO mice as a result of the reduced CSA, whereas the force developed by each myosin molecular motor was unaffected. While the performance by treadmill running was similar in MKO and wild-type mice, MKO mice showed progressively decreased exercise capability, Z-line damage, and signs of muscle regeneration following consecutive days of downhill running. Additionally, MKO muscle exhibited progressive Z-line widening starting from 8 months of age. RNA-sequencing analysis revealed down-regulation of serum response factor (SRF)-target genes in muscles from postnatal MKO mice, important for muscle growth and differentiation. The SRF pathway is regulated by actin dynamics as binding of globular actin to the SRF-cofactor myocardin-related transcription factor A (MRTF-A) prevents its translocation to the nucleus where it binds and activates SRF. MYPN was found to bind and bundle filamentous actin as well as interact with MRTF-A. In particular, while MYPN reduced actin polymerization, it strongly inhibited actin depolymerization and consequently increased MRTF-A-mediated activation of SRF signalling in myogenic cells. Reduced myotube width in MKO primary myoblast cultures was rescued by transduction with constitutive active SRF, demonstrating that MYPN promotes skeletal muscle growth through activation of the SRF pathway.

Conclusions: Myopalladin plays a critical role in the control of skeletal muscle growth through its effect on actin dynamics and consequently the SRF pathway. In addition, MYPN is important for the maintenance of Z-line integrity during exercise and aging. These results suggest that muscle weakness in patients with biallelic MYPN mutations may be associated with reduced myofibre CSA and SRF signalling and that the disease phenotype may be aggravated by exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015241PMC
February 2020

Reach out and grasp the opportunity: reconstructive hand surgery in tetraplegia.

J Hand Surg Eur Vol 2019 May 11;44(4):343-353. Epub 2019 Feb 11.

3 Shirley Ryan Ability Lab, Northwestern University and Hines VA Medical Center Chicago, IL, USA.

Reconstructive upper extremity surgeries in tetraplegia are technically challenging because of the many complicated real-time decisions that need to be made, e.g. extent of release of donor muscle-tendon complex, routing of donor muscles, tissue preparation and optimization, tensioning of muscle-tendon units, balancing joints and suturing tendon-to-tendon attachments. Nerve transfer surgeries can add functionality but also make the reconstruction planning more complex. In this overview, we present some of the fundamental muscle-tendon-joint mechanics studies that allow for single-stage surgical reconstruction of hand function as well as early postoperative activity-based training in patients with cervical spinal cord injuries. We foresee an increased need for studies addressing combined nerve and tendon transfer reconstructions in parallel with patient-perceived outcome investigations. These should be combined with implementation of assistive technology such as functional electrical stimulation for diagnostic, prognostic and training purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1753193419827814DOI Listing
May 2019

Muscle contracture and passive mechanics in cerebral palsy.

J Appl Physiol (1985) 2019 05 20;126(5):1492-1501. Epub 2018 Dec 20.

Swiss Paraplegic Center, Nottwil, Switzerland.

Skeletal muscle contractures represent the permanent shortening of a muscle-tendon unit, resulting in loss of elasticity and, in extreme cases, joint deformation. They may result from cerebral palsy, spinal cord injury, stroke, muscular dystrophy, and other neuromuscular disorders. Contractures are the prototypic and most severe clinical presentation of increased passive mechanical muscle force in humans, often requiring surgical correction. Intraoperative experiments demonstrate that high muscle passive force is associated with sarcomeres that are abnormally stretched, although otherwise normal, with fewer sarcomeres in series. Furthermore, changes in the amount and arrangement of collagen in the extracellular matrix also increase muscle stiffness. Structural light and electron microscopy studies demonstrate that large bundles of collagen, referred to as perimysial cables, may be responsible for this increased stiffness and are regulated by interaction of a number of cell types within the extracellular matrix. Loss of muscle satellite cells may be related to changes in both sarcomeres and extracellular matrix. Future studies are required to determine the underlying mechanism for changes in muscle satellite cells and their relationship (if any) to contracture. A more complete understanding of this mechanism may lead to effective nonsurgical treatments to relieve and even prevent muscle contractures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00278.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589815PMC
May 2019

Biomechanical response of skeletal muscle to eccentric contractions.

Authors:
Richard L Lieber

J Sport Health Sci 2018 Jul 20;7(3):294-309. Epub 2018 Jun 20.

Shirley Ryan Ability Lab, Department of Veterans Affairs, Departments of Biomedical Engineering and Physiology, Northwestern University, Chicago, IL 60611, USA.

The forced lengthening of an activated skeletal muscle has been termed an eccentric contraction (EC). This review highlights the mechanically unique nature of the EC and focuses on the specific disruption of proteins within the cell known as cytoskeletal proteins. The major intermediate filament cytoskeletal protein, desmin, has been the focus of work in this area because changes to desmin occur within minutes of ECs and because desmin has been shown to play both a mechanical and biologic role in a muscle's response to EC. It is hoped that these types of studies will assist in decreasing the incidence of muscle injury in athletes and facilitating the development of new therapies to treat muscle injuries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jshs.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189273PMC
July 2018
-->