Key pointsr Ventilation increases more with chronic than acute hypoxia and does not return to control levels when normoxia is restored, indicating plasticity in the reflexes that control breathing.r Glutamate is the primary excitatory neurotransmitter between arterial chemoreceptors that sense hypoxia and neural circuits that control breathing in the brainstem.r We microinjected specific glutamate receptor antagonists into the brainstem of awake unrestrained rats and found NMDA-type glutamate receptors explain increased ventilatory sensitivity to hypoxia after chronic hypoxia. AMPA-type glutamate receptors mediate increased ventilatory drive in normoxia after chronic hypoxia, as well as increased ventilation in acute hypoxia after chronic hypoxia and in control conditions. r Phosphorylation of AMPA and NMDA receptors is increased by chronic hypoxia. r The results indicate that plasticity in different glutamate receptors have unique effects on the reflexes that control breathing in chronic hypoxia and may share cellular mechanisms with other models of neural plasticity.Abstract When exposed to a hypoxic environment the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time-dependent increase in ventilation occurs, which increases the HVR. This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. Currently these mechanisms of HVR plasticity are unknown and we hypothesized that they involve glutamatergic synapses in the nucleus tractus solitarius (NTS), where afferent endings from arterial chemoreceptors terminate. To test this, we treated rats held in normoxia (CON) or 10% O 2 (CSH) for 7 days and measured ventilation in conscious, unrestrained animals before and after microinjecting glutamate receptor agonists and antagonists into the NTS. In normoxia, AMPA increased ventilation 25% and 50% in CON and CSH, respectively, while NMDA doubled ventilation in both groups (P < 0.05). Specific AMPA and NMDA receptor antagonists (NBQX and MK801, respectively) abolished these effects. MK801 significantly decreased the HVR in CON rats, and completely blocked the acute HVR in CSH rats but had no effect on ventilation in normoxia. NBQX decreased ventilation whenever it was increased relative to normoxic controls; i.e. acute hypoxia in CON and CSH, and normoxia in CSH. These results support our hypothesis that glutamate receptors in the NTS contribute to plasticity in the HVR with CSH. The mechanism underlying this synaptic plasticity is probably glutamate receptor modification, as in CSH rats the expression of phosphorylated NR1 and GluR1 proteins in the NTS increased 35% and 70%, respectively, relative to that in CON rats.

SUMMARY The molecular components largely responsible for muscle attributes such as passive tension development (titin and collagen), active tension development (myosin heavy chain, MHC) and mechanosensitive signaling (titin) have been well studied in animals but less is known about their roles in humans. The purpose of this study was to perform a comprehensive analysis of titin, collagen and MHC isoform distributions in a large number of human muscles, to search for common themes and trends in the muscular organization of the human body. In this study, 599 biopsies were obtained from six human cadaveric donors (mean age 83 years). Three assays were performed on each biopsy – titin molecular mass determination, hydroxyproline content (a surrogate for collagen content) and MHC isoform distribution. Titin molecular mass was increased in more distal muscles of the upper and lower limbs. This trend was also observed for collagen. Percentage MHC-1 data followed a pattern similar to collagen in muscles of the upper extremity but this trend was reversed in the lower extremity. Titin molecular mass was the best predictor of anatomical region and muscle functional group. On average, human muscles had more slow myosin than other mammals. Also, larger titins were generally associated with faster muscles. These trends suggest that distal muscles should have higher passive tension than proximal ones, and that titin size variability may potentially act to ‘tune’ the protein's mechanotransduction capability.

Muscle stiffness after rotator cuff tendon injury is more severe with large tears. This finding supports the concept of early intervention, when tendon tears are smaller, and interventions targeting the extracellular matrix.

Multifidus becomes stiffer, both in individual fibers and fiber bundles, in response to experimentally induced intervertebral disc degeneration. This cannot be explained by change in fiber-type due to reduced muscle use, nor by the increased size of the protein titin (which would reduce stiffness). We hypothesize that fiber bundles become stiffer by proliferation and/or reorganization of collagen content within the muscle but the basis for fiber stiffening is not known.

Abdominal wall muscles have a unique morphology suggesting a complex role in generating and transferring force to the spinal column. Studying passive mechanical properties of these muscles may provide insights into their ability to transfer force among structures. Biopsies from rectus abdominis (RA), external oblique (EO), internal oblique (IO), and transverse abdominis (TrA) were harvested from male Sprague-Dawley rats, and single muscle fibers and fiber bundles (4 to 8 fibers ensheathed in their connective tissue matrix) were isolated and mechanically stretched in a passive state. Slack sarcomere lengths were measured and elastic moduli were calculated from stress-strain data. Titin molecular mass was also measured from single muscle fibers. No significant differences were found among the four abdominal wall muscles in terms of slack sarcomere length or elastic modulus. Interestingly, across all four muscles, slack sarcomere lengths were quite long in individual muscle fibers (> 2.4 µm), and demonstrated a significantly longer slack length in comparison to fiber bundles (p < 0.0001). Also, the extracellular connective tissue matrix provided a stiffening effect and enhanced the resistance to lengthening at long muscle lengths. Titin molecular mass was significantly less in TrA compared to each of the other three muscles (p < 0.0009), but this difference did not correspond to hypothesized differences in stiffness.