| Autor: |
Saldarriaga CA; Department of Anesthesiology and Perioperative Medicine, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States., Alatout MH; Department of Anesthesiology and Perioperative Medicine, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States., Khurram OU; Department of Physiology and Biomedical Engineering, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States., Gransee HM; Department of Anesthesiology and Perioperative Medicine, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States., Sieck GC; Department of Anesthesiology and Perioperative Medicine, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States.; Department of Physiology and Biomedical Engineering, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States., Mantilla CB; Department of Anesthesiology and Perioperative Medicine, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States.; Department of Physiology and Biomedical Engineering, College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, United States. |
| Abstrakt: |
Aging results in increased neuromuscular transmission failure and denervation of the diaphragm muscle, as well as decreased force generation across a range of motor behaviors. Increased risk for respiratory complications in old age is a major health problem. Aging impairs autophagy, a tightly regulated multistep process responsible for clearing misfolded or aggregated proteins and damaged organelles. In motor neurons, aging-related autophagy impairment may contribute to deficits in neurotransmission, subsequent muscle atrophy, and loss of muscle force. Chloroquine is commonly used to inhibit autophagy. We hypothesized that chloroquine decreases transdiaphragmatic pressure (Pdi) in mice. Old mice (16-28 mo old; n = 26) were randomly allocated to receive intraperitoneal chloroquine (50 mg/kg) or vehicle 4 h before measuring Pdi during eupnea, hypoxia (10% O 2 )-hypercapnia (5% CO 2 ) exposure, spontaneous deep breaths ("sighs"), and maximal activation elicited by bilateral phrenic nerve stimulation (Pdi max ). Pdi amplitude and ventilatory parameters across experimental groups and behaviors were evaluated using a mixed linear model. There were no differences in Pdi amplitude across treatments during eupnea (∼8 cm H 2 O), hypoxia-hypercapnia (∼10 cm H 2 O), or sigh (∼36 cm H 2 O), consistent with prior studies documenting a lack of aging effects on ventilatory behaviors. In vehicle and chloroquine-treated mice, average Pdi max was 61 and 46 cm H 2 O, respectively. Chloroquine decreased Pdi max by 24% compared to vehicle ( P < 0.05). There were no sex or age effects on Pdi in older mice. The observed decrease in Pdi max suggests aging-related susceptibility to impairments in autophagy, consistent with the effects of chloroquine on this important homeostatic process. NEW & NOTEWORTHY Recent findings suggest that autophagy plays a role in the development of aging-related neuromuscular dysfunction; however, the contribution of autophagy impairment to the maintenance of diaphragm force generation in old age is unknown. This study shows that in old mice, chloroquine administration decreases maximal transdiaphragmatic pressure generation. These chloroquine effects suggest a susceptibility to impairments in autophagy in old age. |
