scholarly journals Tuning of feedforward control enables stable muscle force-length dynamics after loss of autogenic proprioceptive feedback

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Joanne C Gordon ◽  
Natalie C Holt ◽  
Andrew Biewener ◽  
Monica A Daley
Keyword(s):  
Steady State ◽  
Feedforward Control ◽  
Control Mechanisms ◽  
Leg Muscles ◽  
Similar Work ◽  
Numida Meleagris ◽  
Muscle Dynamics ◽  
Intact Muscle

Animals must integrate feedforward, feedback and intrinsic mechanical control mechanisms to maintain stable locomotion. Recent studies of guinea fowl (Numida meleagris) revealed that the distal leg muscles rapidly modulate force and work output to minimize perturbations in uneven terrain. Here we probe the role of reflexes in the rapid perturbation responses of muscle by studying the effects of proprioceptive loss. We induced bilateral loss of autogenic proprioception in the lateral gastrocnemius muscle (LG) using self-reinnervation. We compared in vivo muscle dynamics and ankle kinematics in birds with reinnervated and intact LG. Reinnervated and intact LG exhibit similar steady state mechanical function and similar work modulation in response to obstacle encounters. Reinnervated LG exhibits 23ms earlier steady-state activation, consistent with feedforward tuning of activation phase to compensate for lost proprioception. Modulation of activity duration is impaired in rLG, confirming the role of reflex feedback in regulating force duration in intact muscle.

scholarly journals Tuning of feedforward control enables stable muscle force-length dynamics after loss of autogenic proprioceptive feedback

2019 ◽  
Author(s):  
JC Gordon ◽  
NC Holt ◽  
AA Biewener ◽  
MA Daley
Keyword(s):  
Feedforward Control ◽  
Control Mechanisms ◽  
Uneven Terrain ◽  
Leg Muscles ◽  
Numida Meleagris ◽  
Muscle Dynamics ◽  
Ankle Kinematics ◽  
Intact Muscle

AbstractAnimals must integrate feedforward, feedback and intrinsic mechanical control mechanisms to maintain stable locomotion. Recent studies of guinea fowl (Numida meleagris) revealed that the distal leg muscles rapidly modulate force and work output to minimize perturbations in uneven terrain. Here we probe the role of reflexes in the rapid perturbation response of muscle by studying the effects of proprioceptive loss. We induced bilateral loss of autogenic proprioception in the lateral gastrocnemius muscle (LG) using self-reinnervation. We compared ankle kinematics and in vivo muscle dynamics in birds with reinnervated LG and intact LG. Reinnervated and intact muscles exhibit similar force-length dynamics, with rapid changes in work to stabilize running obstacle terrain. Reinnervated LG exhibits 23ms earlier steady-state activation, consistent with feedforward tuning of activation phase to compensate for lost proprioception. Modulation of force duration is impaired in rLG, confirming the role of reflex feedback in regulating force duration in intact muscle.

Relationship of Motor Mechanisms to Gastroparesis Symptoms: Towards Individualized Treatment

2021 ◽  
Author(s):  
Michael Camilleri
Keyword(s):  
Animal Studies ◽  
Gastrointestinal Symptoms ◽  
Feedback Regulation ◽  
Individualized Treatment ◽  
Control Mechanisms ◽  
Gastric Accommodation ◽  
Billroth I ◽  
Gastric Sensitivity

Following a classical paper by Dr. Keith A. Kelly published in this journal, and over the past 40 years, there has been increased understanding of the functions of different regions of the stomach, specifically the fundus, antrum, and pylorus. Several of the important physiological principles were based on in vivo animal studies that led to the appreciation of regional function and control mechanisms. These include the roles of the extrinsic parasympathetic vagal innervation, the gastric enteric nervous system and electrical syncytium consisting of pacemaker cells and smooth muscle cells, and duodenogastric reflexes providing feedback regulation following the arrival of food and hydrogen ions stimulating the release of hormones and vagal afferent mechanisms that inhibit gastric motility and stimulate pyloric contractility. Further insights on the role of regional motor functions in gastric emptying were obtained from observations in patients following diverse gastric surgeries or bariatric procedures, including fundoplication, Billroth I and sleeve gastrectomy, and sleeve gastroplasty. Antropyloroduodenal manometry as well as measurements of pyloric diameter and distensibility index provided important assessments of the role of antral hypomotility and pylorospasm, and these constitute specific targets for individualized treatment of patients with gastroparesis. Moreover, in patients with upper gastrointestinal symptoms suggestive of gastroparesis, the availability of measurements of gastric accommodation as well as pharmacological agents to reduced gastric sensitivity or enhance gastric accommodation provide additional specific targets for individualized treatment. It is anticipated that, in the future, such physiological measurements will be applied in patients to optimize choice of therapy, possibly including identifying the best candidate for pyloric interventions.

DPP10 is an inactivation modulatory protein of Kv4.3 and Kv1.4

2006 ◽  
Vol 291 (5) ◽  
pp. C966-C976 ◽  
Author(s):  
Hong-Ling Li ◽  
Yu-Jie Qu ◽  
Yi Chun Lu ◽  
Vladimir E. Bondarenko ◽  
Shimin Wang ◽  
...  
Keyword(s):  
Steady State ◽  
Interacting Protein ◽  
Voltage Gated ◽  
Time To Peak ◽  
Kv Channel ◽  
Closed State ◽  
Channel Inactivation ◽  
Recovery From Inactivation

Voltage-gated K+ channels exist in vivo as multiprotein complexes made up of pore-forming and ancillary subunits. To further our understanding of the role of a dipeptidyl peptidase-related ancillary subunit, DPP10, we expressed it with Kv4.3 and Kv1.4, two channels responsible for fast-inactivating K+ currents. Previously, DPP10 has been shown to effect Kv4 channels. However, Kv1.4, when expressed with DPP10, showed many of the same effects as Kv4.3, such as faster time to peak current and negative shifts in the half-inactivation potential of steady-state activation and inactivation. The exception was recovery from inactivation, which is slowed by DPP10. DPP10 expressed with Kv4.3 caused negative shifts in both steady-state activation and inactivation of Kv4.3, but no significant shifts were detected when DPP10 was expressed with Kv4.3 + KChIP2b (Kv channel interacting protein). DPP10 and KChIP2b had different effects on closed-state inactivation. At −60 mV, KChIP2b nearly abolishes closed-state inactivation in Kv4.3, whereas it developed to a much greater extent in the presence of DPP10. Finally, expression of a DPP10 mutant consisting of its transmembrane and cytoplasmic 58 amino acids resulted in effects on Kv4.3 gating that were nearly identical to those of wild-type DPP10. These data show that DPP10 and KChIP2b both modulate Kv4.3 inactivation but that their primary effects are on different inactivation states. Thus DPP10 may be a general modulator of voltage-gated K+ channel inactivation; understanding its mechanism of action may lead to deeper understanding of the inactivation of a broad range of K+ channels.

BODY ORGAN CYTOCHROME OXIDASE ACTIVITY IN COLD- AND WARM-ACCLIMATED RATS

1963 ◽  
Vol 41 (9) ◽  
pp. 1847-1854 ◽  
Author(s):  
Ladislav Janský
Keyword(s):  
Steady State ◽  
Cytochrome Oxidase ◽  
Oxidase Activity ◽  
Whole Body ◽  
Cytochrome Oxidase Activity ◽  
Full Capacity ◽  
Body Organ ◽  
Total Body

The cytochrome oxidase activity was estimated in homogenates of the whole body and in nine body organs of cold- and warm-acclimated rats. The total body cytochrome oxidase activity expressed in terms of oxygen consumption was similar in cold- and warm-acclimated rats. In cold-acclimated animals the total cytochrome oxidase activity did not differ from maximal steady state metabolism measured in vivo, while in warm-acclimated rats the total cytochrome oxidase activity was almost twice as great as the maximal steady state metabolism. The results indicate that warm-acclimated rats do not utilize the full capacity of the cytochrome system and that cold-acclimation makes full exploitation of the oxidase capacity possible. In cold-acclimated rats the cytochrome oxidase activity of the muscles comprised 57% of the total, the liver 22.5%, and the skin 6%, with smaller roles for other organs. The role of the liver was greater in cold-acclimated than in warm-acclimated rats.

scholarly journals Regulation of steady-state neutrophil homeostasis by macrophages

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 618-629 ◽  
Author(s):  
Claire Gordy ◽  
Heather Pua ◽  
Gregory D. Sempowski ◽  
You-Wen He
Keyword(s):  
Steady State ◽  
Protein C ◽  
Marginal Zone ◽  
Extramedullary Hematopoiesis ◽  
Granulocyte Colony Stimulating Factor ◽  
Inhibitory Protein ◽  
Stimulating Factor ◽  
Defective Clearance

Abstract The timely clearance of apoptotic neutrophils from inflammation sites is an important function of macrophages; however, the role of macrophages in maintaining neutrophil homeostasis under steady-state conditions is less well understood. By conditionally deleting the antiapoptotic gene cellular FLICE-like inhibitory protein (C-FLIP) in myeloid cells, we have generated a novel mouse model deficient in marginal zone and bone marrow stromal macrophages. These mice develop severe neutrophilia, splenomegaly, extramedullary hematopoiesis, decreased body weight, and increased production of granulocyte colony-stimulating factor (G-CSF) and IL-1β, but not IL-17. c-FLIPf/f LysM-Cre mice exhibit delayed clearance of circulating neutrophils, suggesting that failure of macrophages to efficiently clear apoptotic neutrophils causes production of cytokines that drive excess granulopoiesis. Further, blocking G-CSF but not IL-1R signaling in vivo rescues this neutrophilia, suggesting that a G-CSF–dependent, IL-1β–independent pathway plays a role in promoting neutrophil production in mice with defective clearance of apoptotic cells.

scholarly journals Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4283-4290 ◽  
Author(s):  
Michael J. White ◽  
Simone M. Schoenwaelder ◽  
Emma C. Josefsson ◽  
Kate E. Jarman ◽  
Katya J. Henley ◽  
...  
Keyword(s):  
Steady State ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Platelet Production ◽  
Effector Caspase ◽  
Functional Regulation ◽  
Caspase Cascade ◽  
And Function

Abstract Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737–induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9−/− platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.

A Novel Role of Histone Deacetylase 11 (HDAC11) in Regulation of Myeloid-Derived Suppressor Cell (MDSC) Expansion

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2439-2439
Author(s):  
Eva Sahakian ◽  
John Powers ◽  
Jennifer Rock-Klotz ◽  
Marsilio Adriani ◽  
Karrune V. Woan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Steady State ◽  
Transgenic Mice ◽  
Myeloid Cells ◽  
Negative Regulator ◽  
Cell Phenotype ◽  
Variable Expression ◽  
Tumor Bearing

Abstract Abstract 2439 HDAC11 is the newest member of the HDAC family. The physiological role of this HDAC was largely unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in myeloid cells in-vitro1. To better elucidate the role of HDAC11 in these cells, we have utilized an HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allow us to “visualize” dynamic changes in HDAC11 gene expression /transcriptional activity in immune cells in vivo. Immature myeloid cells (IMCs) differentiate into dendritic cells, macrophages, and neutrophils and are also considered to be precursors of MDSCs in tumor-bearing hosts. Here, we show for the first time that HDAC11 plays an important role in this process. First, IMCs from the bone marrow and spleen of TgHDAC11-eGFP mice display high expression of eGFP indicative of HDAC11 transcriptional activation in these cells in the steady state. Subcutaneous injection of PANCO2 tumor cells into these mice resulted in expansion of MDSCs (identified by the expression of CD11b+/GR1+ [Ly6G and Ly6C] with variable expression of CD49d and CD115) in their lymphoid organs which was similar in magnitude to the expansion observed in tumor-bearing wild type (WT) mice. Of note, flow cytometric analysis revealed that expression of eGFP was significantly decreased in the myeloid compartment of tumor bearing TgHDAC11-eGFP mice, suggesting that the transition of IMC into MDSCs might require a decrease in HDAC11 expression. Reminiscent of our findings in the eGFP mice, studies in non-transgenic mice also demonstrated that tumor derived CD11b+ Ly6G+ MDSCs display less HDAC11 mRNA expression. Additional support for the regulatory role of HDAC11 in MDSC expansion/function has been recently provided by our studies in HDAC11KO mice, demonstrating the acquisition of a suppressive cell phenotype, by myeloid cells identical to MDSCs, in the steady state and in the absence of tumor challenge. Taken together, HDAC11 might function as a negative regulator of MDSC expansion/function in vivo. A better understanding of this previously unknown role of HDAC11 in MDSC biology might lead to targeted epigenetic therapies to influence the suppressive abilities of these cells and augment the efficacy of immunotherapeutic approaches against hematologic malignancies. 1. Villagra A, et al. Nat Immunol. 2009 Jan;10(1):92-100 Disclosures: No relevant conflicts of interest to declare.

Relationship of intracellular creatine concentration and uptake to muscle mass in vivo

1978 ◽  
Vol 235 (5) ◽  
pp. C199-C203 ◽  
Author(s):  
W. W. Hofmann ◽  
J. Butte ◽  
H. A. Leon
Keyword(s):  
Isometric Exercise ◽  
Major Change ◽  
Creatine Phosphate ◽  
Control Mechanisms ◽  
Relationship Of ◽  
Developing Muscle ◽  
Hydrolysis Of

Attempts have been made to evaluate the role of intracellular creatine in conditions leading to increased or decreased amounts of contractile protein in rat skeletal muscles. Resting concentrations of intracellular creatine ([Cr]i) and creatine phosphate ([CrP]i) were compared in gastrocnemius and soleus muscles with those immediately after a 20-s tetanic stimulation. The hydrolysis of creatine phosphate was the same after heavily and lightly loaded contractions, suggesting that hypertrophy of isometric exercise is not mediated by creatine. With atrophy after denervation or interruption of sciatic axoplasmic flow [Cr]i also remained unchanged, though [CrP]i and the rate of Cr uptake fell after denervation. The major change in adult red and white muscle bulk with unaltered [Cr]i suggests that the Cr sensitivity found by others in developing muscle in vitro has been supplemented or replaced by other control mechanisms.

Nondominant Arm Advantages in Load Compensation During Rapid Elbow Joint Movements

2003 ◽  
Vol 90 (3) ◽  
pp. 1503-1513 ◽  
Author(s):  
Leia B. Bagesteiro ◽  
Robert L. Sainburg
Keyword(s):  
Muscle Activity ◽  
Considerable Increase ◽  
Feedforward Control ◽  
Elbow Flexion ◽  
Control Mechanisms ◽  
Final Position ◽  
Flexor Muscle ◽  
Load Compensation ◽  
Air Jet

This study was designed to examine interlimb asymmetries in responding to unpredictable changes in inertial loads, which have implications for our understanding of the neural mechanisms underlying handedness. Subjects made repetitive single joint speed constrained 20° elbow flexion movements, while the arm was supported on a horizontal, frictionless, air-jet system. On random trials, a 2-kg mass was attached to the arm splint prior to the “go” signal. Subjects were not given explicit information about the mass prior to movement nor were they able to view their limb or the mass. Accordingly, muscle activity, recorded prior to peak tangential finger acceleration, was the same for loaded and baseline trials. After this point, substantial changes in muscle activity occurred. In both limbs, the load compensation response was associated with a reduction in extensor muscle activity, resulting in a prolonged flexion phase of motion. For the nondominant arm, this resulted in effective load compensation, such that no differences in final position accuracy occurred between loaded and baseline trials. However, the dominant arm response also included a considerable increase in flexor muscle activity. This substantially prolonged the flexor acceleration phase of motion, relative to that of the nondominant arm. As a result, the dominant arm overcompensated the effects of the load, producing a large and systematic overshoot of final position. These results indicate more effective load compensation responses for the nondominant arm; supporting a specialized role of the nondominant arm/hemisphere system in sensory feedback mediated error correction mechanisms. The results also suggest that specialization of the dominant arm system for controlling limb and task dynamics is specifically related to feedforward control mechanisms.

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