Callahan DM, Tourville TW, Miller MS, Hackett SB, Sharma H, Cruickshank NC, Slauterbeck JR, Savage PD, Ades PA, Maughan DW, Beynnon BD, Toth MJ. Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function. Am J Physiol Cell Physiol 308: C932-C943, 2015. First published March 25, 2015; doi:10.1152/ajpcell.00014.2015.-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 ϭ 16) were recruited to reflect the effects of chronic lower extremity muscle disuse and compared with recreationally active controls (n ϭ 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 crosssectional 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. mitochondria; physical activity; ultrastructure; myosin AGING AND DISEASE are frequently accompanied by reduced functional capacity and the development of physical disability (18). Reductions in physical activity with age are well documented (28,60,68) and promote chronic disease (31,44,53) and disability. As a result of their temporal coordination, it is difficult to disentangle the relative influence of age, disease, and physical inactivity on skeletal muscle biology and, in turn, the progression toward physical disability. Indeed, many of the muscle phenotypes that accompany aging and chronic disease, such as atrophy and contractile dysfunction, closely mimic those that accompany muscle disuse (1,46). Whether developed gradually or rapidly following a clinical event, muscle disuse in chronic conditions, such as heart failure or chronic obstructive pulmonary disease, is characterized by its persistent nature, as numerous studies reveal reduced habitual activity levels in these populations (28,60,68). Our understanding of the effects of chronic disuse on skeletal muscle size and structure is limited, in part, by the fact that it would be unethical to experimentally impose ...

No abstract

Brain derived neurotrophic factor (BDNF) is an important modulator of neuronal function, capable of mediating long‐term changes in neuronal structure and signaling in the central nervous system (CNS). Increased expression of BDNF in the PVN has been associated with elevated blood pressure (BP) and sympathetic nervous system activity. However, the mechanism mediating this effect of BDNF is unclear. BDNF is a modulator of catecholaminergic (CA‐ergic) neuronal function in the CNS, and could potentially influence CA‐ergic input to the PVN. The majority of CA‐ergic projections to the PVN come from the nucleus of the solitary tract (NTS), and these projections have been shown to exert a hypotensive effect. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates BP in part by diminishing the inhibitory input from NTS CA‐ergic neurons projecting to the PVN by downregulating β‐receptors in the PVN. Sprague‐Dawley (SD) rats received bilateral PVN injections of AAV2 viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of phosphate‐buffered saline (PBS) or anti‐dopamine‐β‐hydroxylase‐conjugated saporin (DSAP), a neurotoxin selective to noradrenaline‐ and adrenaline‐synthesizing neurons. BDNF overexpression in the PVN without lesioning NTS CAergic neurons significantly increased mean arterial pressure (MAP) (BDNF+PBS: 115±3 mmHg, p<0.01 vs GFP+PBS: 96±2 mmHg). DSAP treatment increased MAP in the GFP group by ~13 mmHg, whereas DSAP treatment in the BDNF group did not significantly alter MAP. This suggests that BDNF overexpression in the PVN may interfere with CA‐ergic communication between the NTS and PVN. Since previous reports suggested that adrenergic β‐receptors exert an inhibitory effect on PVN neurons and lower BP, we tested whether BDNF overexpression in the PVN diminishes hypotensive effects of β‐receptor activation in the PVN. SD rats received bilateral PVN injections of AAV2 viral vectors expressing either GFP or BDNF. Three weeks later, BP responses to an injection of Isoprenaline (125 μM or 250 μM), a non‐selective β‐adrenergic agonist, into the PVN were recorded under alpha chloralosed‐urethane anesthesia. Our results showed that BDNF treatment significantly attenuated MAP responses to Isoprenaline compared to the GFP group in a dose dependent manner. In the GFP group, peak decrease in MAP in response to 125 μM and 250 μM Iso was −21±4 mmHg and −29±4 mmHg, compared with −4±1 mmHg (p<0.01) and −8±1 mmHg (p<0.001) in the BDNF group. To test if the reduced effect of Isoprenaline is due to a BDNF‐induced change in adrenergic receptor expression in the PVN, we assessed adrenergic receptor expression using quantitative RT‐PCR in PVN brain punches from SD rats previously injected with an AAV2 viral vectors expressing either GFP or BDNF. BDNF treatment significantly reduced the expression of β1 adrenergic receptor mRNA expression, whereas α1a, α1b, α2a, and β2 adrenergic receptors were unaffected by BDNF treatment. In summary, our findings indicate ...

Brain derived neurotrophic factor (BDNF) is an important modulator of neuronal function, capable of mediating long‐term changes in neuronal structure and signaling in the central nervous system (CNS). Increased expression of BDNF in the PVN has been associated with elevated blood pressure (BP) and sympathetic nervous system activity. However, the mechanism mediating this effect of BDNF is unclear. BDNF is a modulator of catecholaminergic (CA‐ergic) neuronal function in the CNS, and could potentially influence CA‐ergic input to the PVN. The majority of CA‐ergic projections to the PVN come from the nucleus of the solitary tract (NTS), and these projections have been shown to exert a hypotensive effect. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates BP in part by diminishing the inhibitory input from NTS CA‐ergic neurons projecting to the PVN by downregulating β‐receptors in the PVN. Sprague‐Dawley (SD) rats received bilateral PVN injections of AAV2 viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of phosphate‐buffered saline (PBS) or anti‐dopamine‐β‐hydroxylase‐conjugated saporin (DSAP), a neurotoxin selective to noradrenaline‐ and adrenaline‐synthesizing neurons. BDNF overexpression in the PVN without lesioning NTS CAergic neurons significantly increased mean arterial pressure (MAP) (BDNF+PBS: 115±3 mmHg, p<0.01 vs GFP+PBS: 96±2 mmHg). DSAP treatment increased MAP in the GFP group by ~13 mmHg, whereas DSAP treatment in the BDNF group did not significantly alter MAP. This suggests that BDNF overexpression in the PVN may interfere with CA‐ergic communication between the NTS and PVN. Since previous reports suggested that adrenergic β‐receptors exert an inhibitory effect on PVN neurons and lower BP, we tested whether BDNF overexpression in the PVN diminishes hypotensive effects of β‐receptor activation in the PVN. SD rats received bilateral PVN injections of AAV2 viral vectors expressing either GFP or BDNF. Three weeks later, BP responses to an injection of Isoprenaline (125 μM or 250 μM), a non‐selective β‐adrenergic agonist, into the PVN were recorded under alpha chloralosed‐urethane anesthesia. Our results showed that BDNF treatment significantly attenuated MAP responses to Isoprenaline compared to the GFP group in a dose dependent manner. In the GFP group, peak decrease in MAP in response to 125 μM and 250 μM Iso was −21±4 mmHg and −29±4 mmHg, compared with −4±1 mmHg (p<0.01) and −8±1 mmHg (p<0.001) in the BDNF group. To test if the reduced effect of Isoprenaline is due to a BDNF‐induced change in adrenergic receptor expression in the PVN, we assessed adrenergic receptor expression using quantitative RT‐PCR in PVN brain punches from SD rats previously injected with an AAV2 viral vectors expressing either GFP or BDNF. BDNF treatment significantly reduced the expression of β1 adrenergic receptor mRNA expression, whereas α1a, α1b, α2a, and β2 adrenergic receptors were unaffected by BDNF treatment. In summary, our findings indicate that increased BDNF expression in the PVN may disrupt CA‐ergic signaling between the NTS and PVN by downregulating β‐receptors in the PVN.Support or Funding InformationSupported by R01 HL133211‐01A1, AHA 11SDG7560022, and UVM start‐up funds.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.