By 2030, ~70 million people in the USA will be >65 years of age and ~10 million will be >85 years old. With aging of our population, there will be an increased incidence of age-related muscle wasting and weakness (sarcopenia), which is a significant predictor of chronic disease and mortality in the elderly. Previously, we found that sarcopenia affects the diaphragm muscle (DIAm) with atrophy of more fatigable type IIx and/or IIb muscle fibers, and a reduction in maximum specific force, making the DIAm considerably weaker in old age. Important to the proposed studies, we found that in older rats there are fewer large phrenic motor neurons (PMNs) that comprise more fatigable motor units. This raises the intriguing possibility that DIAm sarcopenia results from the loss of larger PMNs, leading to denervation of type IIx and/or IIb muscle fibers and DIAm weakness. In support, we found that DIAm sarcopenia is associated with impaired performance of higher force airway clearance behaviors (e.g., coughing, sneezing), which may underlie the increased risk of airway infections in older adults. Premise: The underlying cause of age-related PMN loss is unclear. Certainly with breathing, smaller PMNs are recruited more frequently, and thus their energy demands are higher. Accordingly, it is not surprising that in preliminary studies, we found that mitochondria in smaller PMNs are more fused and have a higher volume density. In diseases such as amyotrophic lateral sclerosis (ALS), mitochondrial fragmentation appears to precede the loss of motor neurons, which is associated with decreased Mfn2 and increased Drp1 expression. Indeed, experimental interventions that support mitochondrial fusion or inhibit fission appear to ameliorate motor neuron dysfunction and degeneration in ALS models. It is also important to note that brain-derived neurotropic factor (BDNF) signaling through its high affinity receptor (TrkB.Fl) promotes motor neuron survival, and mitochondrial fusion, suggesting there may be a link. In support, TrkB.Fl is co-localized to the mitochondrial outer membrane, and in preliminary studies we found that enhanced BDNF/TrkB signaling promotes mitochondrial fusion in NSC34 cultured motor neurons. Conceptual Framework: We hypothesize that the age-related loss of larger PMNs is related to mitochondrial fragmentation, which results from decreased Mfn2 and increased Drp1 expression, and is mitigated by enhanced BDNF/TrkB signaling.
Specific Aim 1 : To test the hypothesis that size-dependent differences in mitochondrial morphology in PMNs are exacerbated with aging and relate to differences in Mfn2 and Drp1 expression.
Specific Aim 2 : To test the hypothesis that the age-related loss of larger PMNs is related to mitochondrial fragmentation, which results from decreased Mfn2 and increased Drp1 expression.
Specific Aim 3 : To test the hypothesis that enhanced BDNF/TrkB.Fl signaling in PMNs mitigates age-related PMN loss, through an effect on Mfn2 and Drp1 expression and mitochondrial morphology.
By 2030, ~70 million people in the USA will be >65 years of age and ~10 million will be >85 years old. With this aging of our population, there will be greater incidence of age-related muscle wasting and weakness (sarcopenia), which is a significant predictor of chronic disease and mortality in the elderly. The diaphragm muscle is the most important inspiratory muscle but it is also susceptible to sarcopenia, which may limit the performance of higher force expulsive airway clearance behaviors such as coughing and sneezing. As a result, this may underlie the increased risk of airway infections in older adults. The proposed studies will examine the neural mechanisms underlying diaphragm muscle sarcopenia and explore the development of novel therapies to mitigate sarcopenia.
| Mantilla, Carlos B; Zhan, Wen-Zhi; Gransee, Heather M et al. (2018) Phrenic motoneuron structural plasticity across models of diaphragm muscle paralysis. J Comp Neurol 526:2973-2983 |
| Gonzalez Porras, Maria A; Sieck, Gary C; Mantilla, Carlos B (2018) Impaired Autophagy in Motor Neurons: A Final Common Mechanism of Injury and Death. Physiology (Bethesda) 33:211-224 |
| Fogarty, Matthew J; Omar, Tanya S; Zhan, Wen-Zhi et al. (2018) Phrenic motor neuron loss in aged rats. J Neurophysiol 119:1852-1862 |
| Khurram, Obaid U; Fogarty, Matthew J; Sarrafian, Tiffany L et al. (2018) Impact of aging on diaphragm muscle function in male and female Fischer 344 rats. Physiol Rep 6:e13786 |
| Jimenez-Ruiz, Federico; Khurram, Obaid U; Zhan, Wen-Zhi et al. (2018) Diaphragm muscle activity across respiratory motor behaviors in awake and lightly anesthetized rats. J Appl Physiol (1985) 124:915-922 |
| Fogarty, Matthew J; Mantilla, Carlos B; Sieck, Gary C (2018) Breathing: Motor Control of Diaphragm Muscle. Physiology (Bethesda) 33:113-126 |
| Khurram, Obaid U; Sieck, Gary C; Mantilla, Carlos B (2017) Compensatory effects following unilateral diaphragm paralysis. Respir Physiol Neurobiol 246:39-46 |
| Gonzalez Porras, Maria A; Durfee, Paul N; Gregory, Ashley M et al. (2016) A novel approach for targeted delivery to motoneurons using cholera toxin-B modified protocells. J Neurosci Methods 273:160-174 |
| Greising, Sarah M; Mantilla, Carlos B; Sieck, Gary C (2016) Functional Measurement of Respiratory Muscle Motor Behaviors Using Transdiaphragmatic Pressure. Methods Mol Biol 1460:309-19 |
| Elliott, Jonathan E; Greising, Sarah M; Mantilla, Carlos B et al. (2016) Functional impact of sarcopenia in respiratory muscles. Respir Physiol Neurobiol 226:137-46 |
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