Vang, Pangdra

The population at very old age is increasing dramatically throughout the world. Aging adults experience increased health and medical needs associated with debility and sarcopenia (i.e., muscle atrophy and force loss). Respiratory complications and diseases are common causes of morbidity and mortality in the elderly. Sarcopenia of respiratory muscles such as the diaphragm muscle (DIAm) may contribute to respiratory complications since the DIAm, the main inspiratory muscle in mammals, plays an important role in ventilation and generating the forces necessary to maintain airway clearance. Presently, there is limited information about aging effects into very old age. Specifically, whether DIAm sarcopenia is exacerbated in old age and if it will effect ventilation into very old age are presently unknown. We hypothesized that DIAm sarcopenia in very old mice (>30 mo; ~30% survival) will result in reduced DIAm force generation across motor behaviors, exhibit impaired ventilation, decreased isometric force, and reduced fiber cross‐sectional area compared to old (24 mo; ~80% survival), and young (6 mo, 100% survival). C57BL/6 × 129 female and male mice (n = 30) at 6 mo, 24 mo, and >30 mo were used to examine transdiaphragmatic pressure (Pdi) generation during eupnea, exposure to hypoxia‐hypercapnia, as well as higher force behaviors in airway occlusion, and/or bilateral phrenic stimulation. Ventilation was assessed using whole body plethysmography and venous blood gases. Isometric force was examined via physiological muscle force testing, and fiber cross‐sectional area was determined in immunohistochemically labeled sections across fiber types. There was a significant reduction in Pdi between young and old mice for higher force behaviors – tracheal occlusion and bilateral phrenic nerve stimulation, (p < 0.001); however, there was no further decline in Pdi for all behaviors between old and very old mice. There was no evidence of impaired ventilation (ventilatory parameters – respiratory rate, minute ventilation, or tidal volume) across age groups, and no evidence of differences between sex in any of the measurements. A loss of ability to generate higher levels of force necessary to maintain airway clearance may predispose older individuals to recurrent infection. Understanding the mechanisms of sarcopenia in old age will be important in mitigating the effects of aging on quality of life and maintaining the health span. Support or Funding Information This work was supported by grants R25‐GM075148, R01‐AG044615, and R01‐AG057052 from the National Institutes of Health. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Mid‐cervical spinal cord contusion injury results in tissue damage, disruption of spinal pathways, and motoneuron loss. Phrenic motoneurons located in C3–5 segments of the cervical spinal cord innervate the diaphragm muscle (DIAm), and unilateral C4 contusion results in loss of 40–50% of motoneurons ipsilateral to the injury (~25% of the total motoneuron pool). Over time after unilateral C4 spinal cord contusion injury, DIAm electromyography (EMG) increases both contralateral and ipsilateral to the side of injury, suggesting compensation due to an increased activation of the surviving motoneurons. However, whether C4 contusion impairs the ability of the DIAm to accomplish higher force motor behaviors is unknown. Transdiaphragmatic pressure (Pdi) was measured across motor behaviors over time after unilateral C4 contusion injury. Maximum Pdi (Pdi max ) was elicited by bilateral phrenic nerve stimulation at 7 days post‐injury. We hypothesized that Pdi max is reduced following C4 mid‐cervical contusion injury, which will constrain the Pdi generated during different motor behaviors. Since ventilatory behaviors of the DIAm require <50% Pdi max , we further hypothesized that Pdi generated during ventilatory behaviors of the DIAm is not impaired after unilateral C4 mid‐cervical spinal cord contusion injury. In support of our hypothesis, we observed that Pdi max was reduced by ~25% after C4 mid‐cervical spinal cord contusion injury compared to a laminectomy control group. This decrease in Pdi max is consistent with the extent of phrenic motoneuron loss following contusion injury. We also found that during both eupnea (quiet breathing) and breathing stimulated by 10% O 2 (hypoxia) and 5% CO 2 (hypercapnia), Pdi generation was unimpaired by C4 mid‐cervical spinal cord contusion injury, again consistent with the lower force requirement of these ventilatory motor behaviors. Prior to injury, Pdi generated during airway occlusion was ~40% of Pdi max . One day following contusion injury, the Pdi amplitude during airway occlusion was reduced from ~30 cm H 2 O to ~20 cm, but this reduction was completely reversed by 7 days post‐injury. The reduction in Pdi amplitude at one day post‐injury cannot be attributed to the ~25% loss of phrenic motoneurons, and thus, may reflect a disruption of input to phrenic motoneurons or acute inflammation of their surrounding milieu. Over time after injury, changes in the balance between inhibition and excitation may result in recovery of higher‐force behaviors. Support or Funding Information Funded by NIH R01‐HL096750 and T32‐HL105355 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Midcervical spinal cord contusion injury results in tissue damage, disruption of spinal pathways, and motor neuron loss. Unilateral C4 contusion results in loss of 40%–50% of phrenic motor neurons ipsilateral to the injury (~25% of the total phrenic motor neuron pool). Over time after unilateral C4 contusion injury, diaphragm muscle (DIAm) electromyogram activity increases both contralateral and ipsilateral to the side of injury in rats, suggesting compensation because of increased activation of the surviving motor neurons. However, the impact of contusion injury on DIAm force generation is less clear. Transdiaphragmatic pressure (Pdi) was measured across motor behaviors over time after unilateral C4 contusion injury in adult male Sprague-Dawley rats. Maximum Pdi (Pdimax) was elicited by bilateral phrenic nerve stimulation at 7 days postinjury. We hypothesized that Pdimaxis reduced following unilateral C4 contusion injury, whereas ventilatory behaviors of the DIAm are unimpaired. In support of our hypothesis, Pdimaxwas reduced by ~25% after unilateral C4 contusion, consistent with the extent of phrenic motor neuron loss following contusion injury. One day after contusion injury, the Pdi amplitude during airway occlusion was reduced from ~30 to ~20 cmH2O, but this reduction was completely reversed by 7 days postinjury. Ventilatory behaviors (~10 cmH2O), DIAm-specific force, and muscle fiber cross-sectional area did not differ between the laminectomy and contusion groups. These results indicate that the large reserve capacity for DIAm force generation allows for higher-force motor behaviors to be accomplished despite motor neuron loss, likely reflecting changes in motor unit recruitment.NEW & NOTEWORTHY Respiratory muscles such as the diaphragm generate the pressures necessary to accomplish a variety of motor behaviors ranging from ventilation to near-maximal expulsive behaviors. However, the impact of contusion injury on diaphragm pressure generation across behaviors is not clear. The present study shows that contusion injury impairs maximal pressure generation while preserving the ability of the diaphragm to accomplish lower-force motor behaviors, likely reflecting changes in diaphragm motor unit recruitment.