BDNF downregulates ß-adrenergic receptor-mediated hypotensive mechanisms in the paraventricular nucleus of the hypothalamus.

Brain-derived neurotrophic factor (BDNF) is upregulated in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli such as stress and hyperosmolality, and BDNF acting in the PVN plays a key role in elevating sympathetic activity and blood pressure. However, downstream mechanisms mediating these effects remain unclear. We tested the hypothesis that BDNF increases blood pressure, in part by diminishing inhibitory hypotensive input from nucleus of the solitary tract (NTS) catecholaminergic neurons projecting to the PVN. Male Sprague-Dawley rats received bilateral PVN injections of viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of vehicle or anti-dopamine-ß-hydroxylase-conjugated saporin (DSAP), a neurotoxin that selectively lesions noradrenergic and adrenergic neurons. BDNF overexpression in the PVN without NTS lesioning significantly increased mean arterial pressure (MAP) in awake animals by 18.7 ± 1.8 mmHg. DSAP treatment also increased MAP in the GFP group, by 9.8 ± 3.2 mmHg, but failed to affect MAP in the BDNF group, indicating a BDNF-induced loss of NTS catecholaminergic hypotensive effects. In addition, in α-chloralose-urethane-anesthetized rats, hypotensive responses to PVN injections of the ß-adrenergic agonist isoprenaline were significantly attenuated by BDNF overexpression, whereas PVN injections of phenylephrine had no effect on blood pressure. BDNF treatment was also found to significantly reduce ß1-adrenergic receptor mRNA expression in the PVN, whereas expression of other adrenergic receptors was unaffected. In summary, increased BDNF expression in the PVN elevates blood pressure, in part by downregulating ß-receptor signaling and diminishing hypotensive catecholaminergic input from the NTS to the PVN.NEW & NOTEWORTHY We have shown that BDNF, a key hypothalamic regulator of blood pressure, disrupts catecholaminergic signaling between the NTS and the PVN by reducing the responsiveness of PVN neurons to inhibitory hypotensive ß-adrenergic input from the NTS. This may be occurring partly via BDNF-mediated downregulation of ß1-adrenergic receptor expression in the PVN and results in an increase in blood pressure.

Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function.

In older adults, we examined the effect of chronic muscle disuse on skeletal muscle structure at the tissue, cellular, organellar, and molecular levels and its relationship to muscle function. Volunteers with advanced-stage knee osteoarthritis (OA, n = 16) were recruited to reflect the effects of chronic lower extremity muscle disuse and compared with recreationally active controls (n = 15) without knee OA but similar in age, sex, and health status. In the OA group, quadriceps muscle and single-fiber cross-sectional area were reduced, with the largest reduction in myosin heavy chain IIA fibers. Myosin heavy chain IIAX fibers were more prevalent in the OA group, and their atrophy was sex-specific: men showed a reduction in cross-sectional area, and women showed no differences. Myofibrillar ultrastructure, myonuclear content, and mitochondrial content and morphology generally did not differ between groups, with the exception of sex-specific adaptations in subsarcolemmal (SS) mitochondria, which were driven by lower values in OA women. SS mitochondrial content was also differently related to cellular and molecular functional parameters by sex: greater SS mitochondrial content was associated with improved contractility in women but reduced function in men. Collectively, these results demonstrate sex-specific structural phenotypes at the cellular and organellar levels with chronic disuse in older adults, with novel associations between energetic and contractile systems.