Department of Physical Therapy & McKnight Brain Institute, Breathing Research and Therapeutics Center, University of Florida, Gainesville, Florida, United States.
J Appl Physiol (1985). 2023 Jun 1;134(6):1537-1548. doi: 10.1152/japplphysiol.00197.2023. Epub 2023 May 11.
Moderate acute intermittent hypoxia (mAIH) elicits a form of spinal, respiratory motor plasticity known as phrenic long-term facilitation (pLTF). In middle-aged male and geriatric female rats, mAIH-induced pLTF is attenuated through unknown mechanisms. In young adults, mAIH activates competing intracellular signaling cascades, initiated by serotonin 2 and adenosine 2A (A) receptors, respectively. Spinal A receptor inhibition enhances mAIH-induced pLTF, meaning, serotonin dominates, and adenosine constrains mAIH-induced plasticity in the daily rest phase. Thus, we hypothesized elevated basal adenosine levels in the ventral cervical spinal cord of aged rats shifts this balance, undermining mAIH-induced pLTF. A selective A receptor antagonist (MSX-3) or vehicle was delivered intrathecally at C4 in anesthetized young (3-6 mo) and aged (20-22 mo) Sprague-Dawley rats before mAIH (3,5-min episodes; arterial Po = 45-55 mmHg). In young males, spinal A receptor inhibition enhanced pLTF (119 ± 5%) vs. vehicle (55 ± 9%), consistent with prior reports. In old males, pLTF was reduced to 25 ± 11%, but A receptor inhibition increased pLTF to levels greater than in young males (186 ± 19%). Basal adenosine levels in ventral C3-C5 homogenates are elevated two- to threefold in old vs. young males. These findings advance our understanding of age as a biological variable in phrenic motor plasticity and will help guide translation of mAIH as a therapeutic modality to restore respiratory and nonrespiratory movements in older populations afflicted with clinical disorders that compromise movement. Advanced age undermines respiratory motor plasticity, specifically phrenic long-term facilitation (pLTF) following moderate acute intermittent hypoxia (mAIH). We report that spinal adenosine increases in aged male rats, undermining mAIH-induced pLTF via adenosine 2A (A) receptor activation, an effect reversed by selective spinal adenosine 2A receptor inhibition. These findings advance our understanding of mechanisms that impair neuroplasticity, and the ability to compensate for the onset of lung or neural injury with age, and may guide efforts to harness mAIH as a treatment for clinical disorders that compromise breathing and other movements.
中度急性间歇性低氧（mAIH）引发一种称为膈神经长期易化（pLTF）的脊髓呼吸运动可塑性。在中年雄性和老年雌性大鼠中，mAIH 诱导的 pLTF 会通过未知机制减弱。在年轻成年人中，mAIH 通过分别由 5-羟色胺 2 和腺苷 2A（A）受体启动的竞争细胞内信号级联反应而被激活。脊髓 A 受体抑制增强了 mAIH 诱导的 pLTF，这意味着 5-羟色胺占主导地位，而腺苷则限制了日常休息阶段 mAIH 诱导的可塑性。因此，我们假设年龄较大的大鼠腹侧颈脊髓中的基础腺苷水平升高会改变这种平衡，从而破坏 mAIH 诱导的 pLTF。在接受麻醉的年轻（3-6 个月）和老年（20-22 个月）Sprague-Dawley 大鼠的 C4 处鞘内给予选择性 A 受体拮抗剂（MSX-3）或载体后，进行 mAIH（3、5 分钟的发作；动脉 Po=45-55mmHg）。在年轻雄性中，脊髓 A 受体抑制增强了 pLTF（119±5%）与载体（55±9%），这与先前的报道一致。在老年雄性中，pLTF 降低至 25±11%，但 A 受体抑制使 pLTF 增加至超过年轻雄性的水平（186±19%）。与年轻雄性相比，老年雄性的腹侧 C3-C5 匀浆中的基础腺苷水平升高了两到三倍。这些发现提高了我们对年龄作为呼吸运动可塑性的生物学变量的认识，并将有助于指导 mAIH 的转化，作为一种治疗方式，以恢复患有临床疾病的老年人群的呼吸和非呼吸运动，这些疾病会损害运动。年龄较大会破坏呼吸运动的可塑性，特别是中度急性间歇性低氧（mAIH）后膈神经的长期易化（pLTF）。我们报告说，在老年雄性大鼠中，脊髓腺苷增加，通过腺苷 2A（A）受体激活破坏 mAIH 诱导的 pLTF，这一效应可通过选择性脊髓腺苷 2A 受体抑制来逆转。这些发现提高了我们对损害神经可塑性的机制的认识，以及随着年龄的增长，对肺或神经损伤的代偿能力，并且可能指导利用 mAIH 作为治疗会损害呼吸和其他运动的临床疾病的治疗方法。
