Journal of Physiology-London最新文献

Transition of the fetus to extrauterine life requires increased cardiac workload and skeletal muscle activity, yet little is known about microvasculature growth during the perinatal period. We collected hindlimb skeletal muscles and cardiac left (LV) and right ventricles (RV) from fetal (135 days of gestational age; 135D) and neonatal (postnatal days 1 and 5; PD1 and PD5) lambs to measure vascular structures by immunofluorescence and expression of angiogenesis regulators. Heart and skeletal muscle weights and myofibre cross-sectional areas were greater in neonatal compared to fetal lambs. The proportion of slow-twitch oxidative myofibres in tibialis anterior (TA) and flexor digitorum superficialis (FDS) was greater in neonatal compared to fetal lambs. Vascularity in TA was 34% lower on PD1 (P = 0.0005) and 26% lower on PD5 (P = 0.00522) compared to 135D, and capillary density was 36% lower on PD5 compared to 135D (P = 0.0007). Similarly, vascularity in FDS was 40% lower on PD1 (P = 0.0003) and 45% lower on PD5 (P = 0.0001) compared to 135D. In RV and LV, vascularity was similar among age groups, but vessel density was 29% lower in LV on PD1 (P = 0.0001) and 40% lower on PD5 (P < 0.0001) compared to 135D. Several genes involved in angiogenesis were downregulated in neonatal compared to fetal muscle and LV, though VEGFA and VEGFR1 protein expression was higher. Striated muscle growth across the perinatal period is equivalent or greater than its microvascular expansion. Postnatal VEGFA protein expression may herald an increase in angiogenesis known to occur beyond the first week of life to meet ongoing striated muscle demand. KEY POINTS: Physiological changes at birth support increased cardiac workload and skeletal muscle activity in the neonate. Previous work in vivo showed that striated muscle perfusion was reduced in neonatal lambs compared to late gestation fetuses in the context of a marked increase in the partial pressure of oxygen upon breathing. Despite an increase in striated muscle size and a greater proportion of slow-twitch oxidative myofibres across the perinatal period, vascularity and microvessel density were either unchanged or reduced in several skeletal muscles and left and right cardiac ventricles of neonatal compared to late gestation fetal lambs. Our results indicate that under normal physiological conditions, striated muscle growth across the perinatal period is equivalent or greater than its microvascular expansion. Future investigations are warranted to determine how an adverse intrauterine environment or an abnormal birth transition may impact skeletal and cardiac microvascular growth.

Calmodulin (CaM) is the principal calcium (Ca²⁺) sensor in eukaryotic cells, orchestrating hundreds of signalling pathways that regulate excitability, contraction, secretion, gene expression and many other essential processes. This small, highly conserved protein binds four Ca²⁺ ions and undergoes conformational changes that enable versatile interactions with a wide range of effector proteins, including numerous ion channels. Among these the transient receptor potential (TRP) channels constitute the second-largest family of cation channels and respond to diverse chemical, mechanical and thermal stimuli. Although TRP channels share a conserved transmembrane core their variable cytosolic domains confer extensive regulatory diversity and tissue-specific function. Across the TRP superfamily CaM acts as a widespread yet mechanistically diverse modulator, with at least one CaM-regulated member in four of the six major subfamilies. In most cases CaM exerts an inhibitory, Ca²⁺-dependent braking mechanism that promotes channel closure or desensitization, contrasting with the activating or anti-inactivating roles CaM plays in several other ion channel families. This review integrates structural, biochemical and functional evidence from eight representative TRP channels to identify common motifs and mechanisms that define CaM-dependent regulation. By mapping known CaM-binding elements onto available cryo-EM structures we contextualize current models of TRP channel calmodulation and highlight structural principles that unify otherwise disparate regulatory behaviours. This structure-guided framework highlights emerging mechanistic themes, details unresolved questions and suggests new hypotheses for how CaM shapes TRP channel function across diverse cellular contexts.

Muscle vibration alters both perceived limb position and velocity by increasing muscle spindle afferent firing rates. In particular the type Ia afferents are affected, which mainly encode muscle stretch velocity. Predictive frameworks of sensorimotor control, such as Active Inference and Optimal Feedback Control, suggest that velocity signals should inform position estimates. Such a function would predict that errors in perceived limb position and velocity should be correlated, but this prediction remains empirically underexplored. We hypothesised that an online evaluation of the integral of sensed velocity influences the perceived arm position during active movements. Using a virtual reality-based reaching task we investigated how vibration-biased proprioceptive feedback influences voluntary movement control and inference of arm position and movement. Our results suggest that muscle vibration biases perceived movement velocity, with downstream effects on perceived limb position and reflexive corrections of movement speed. We found that (i) antagonist vibration during active movement caused participants to overestimate their movement speed while also slowing down, (ii) movement speed and endpoint errors were correlated, with muscle vibration affecting both in congruent directions and (iii) adjustments in movement speed to muscle vibration are sufficiently fast to be reflexive. Together these findings support the hypothesis that proprioceptive velocity signals are integrated to augment inference of position, consistent with predictive frameworks of sensorimotor control. KEY POINTS: During movement without visual feedback, the central nervous system (CNS) has access to both position- and velocity-based proprioceptive signals, which are used to estimate limb state. Muscle vibration biases the perception of limb position, as seen in the classically observed pattern of biased endpoint errors, through the stimulation of primary (type Ia) muscle spindles, primarily a velocity sensor. We investigated how proprioceptive velocity signals affect position estimation during movement by applying muscle vibration while measuring perceived movement speed, actual movement speed and endpoint errors in a virtual reality (VR)-based reaching task. We show that errors in perceived limb position and velocity are correlated during active movements, consistent with predictive frameworks of sensorimotor control. These findings support the idea that the CNS maintains a self-consistent estimate of limb state across both position and velocity domains.