Diaphragm Muscle Adaptation to Sustained Hypoxia: Lessons from Animal Models with Relevance to High Altitude and Chronic Respiratory Diseases

Abstract

The diaphragm is the primary inspiratory pump muscle of breathing. Notwithstanding its critical role in pulmonary ventilation, the diaphragm like other striated muscles is malleable in response to physiological and pathophysiological stressors, with potential implications for the maintenance of respiratory homeostasis. This review considers hypoxic adaptation of the diaphragm muscle, with a focus on functional, structural, and metabolic remodeling relevant to conditions such as high altitude and chronic respiratory disease. On the basis of emerging data in animal models, we posit that hypoxia is a significant driver of respiratory muscle plasticity, with evidence suggestive of both compensatory and deleterious adaptations in conditions of sustained exposure to low oxygen. Cellular strategies driving diaphragm remodeling during exposure to sustained hypoxia appear to confer hypoxic tolerance at the expense of peak force-generating capacity, a key functional parameter that correlates with patient morbidity and mortality. Changes include, but are not limited to: redox-dependent activation of hypoxia-inducible factor (HIF) and MAP kinases; time-dependent carbonylation of key metabolic and functional proteins; decreased mitochondrial respiration; activation of atrophic signaling and increased proteolysis; and altered functional performance. Diaphragm muscle weakness may be a signature effect of sustained hypoxic exposure. We discuss the putative role of reactive oxygen species as mediators of both advantageous and disadvantageous adaptations of diaphragm muscle to sustained hypoxia, and the role of antioxidants in mitigating adverse effects of chronic hypoxic stress on respiratory muscle function.

Respiratory muscle dysfunction in animal models of hypoxic disease: antioxidant therapy goes from strength to strength

“…In stark contrast to CIH models, a pronounced time-dependent redox stress characterizes functional impairments in mouse upper airway77 and diaphragm34,75 muscles in response to CSH stress. Redox modulation of upper airway muscle metabolism and function, which appears hypoxia inducible factor-1 alpha (HIF-1α)-independent,77 gives rise to pronounced muscle weakness without proteolytic degradation, notwithstanding the substantial temporal increase in muscle protein carbonyl content, which, as revealed by two-dimensional proteomic analysis, ranges from mitochondria to the cross-bridges 77.…”

“…Empirically, hypoxia is a major driver of respiratory system plasticity (Table 1). This includes potential for adaptive or compensatory plasticity in respiratory muscle that serves to protect against the challenge of oxygen deficit as well as the contemporaneous capacity to drive aberrant remodeling, which can further exacerbate and perpetuate respiratory dysfunction 27,34,35…”

“…Exposure to 10% inspired oxygen for 4 weeks in mice decreased diaphragm muscle fiber cross-sectional areas and improved mitochondrial aerobic efficiency, likely contributing to the maintenance of diaphragm endurance 73. CSH decreasing diaphragm muscle fiber cross-sectional areas in rat7,74 and mouse73 could be viewed as advantageous in decreasing oxygen diffusion distance 34,73. On the other hand, evidence points to consequential time-dependent and substantial loss of force-generating capacity,7,75 which is also consistent with decreased fiber cross-sectional areas 7,73.…”

“…Pronounced metabolic remodeling occurs in CSH mouse diaphragm, which may be partly HIF-1α-dependent and thus redox-dependent,75 with altered mitochondrial respiration rates,73 decreased oxidative and glycolytic enzyme activities, and an apparent increased reliance on fatty acid metabolism 75. The redox-dependent plasticity confers early adaptive responses,7,73,75,89 which culminate in time-dependent diaphragm weakness, perhaps a tradeoff for cellular adaptive responses improving hypoxic tolerance 34,75. Lewis and O’Halloran34 have recently provided a review of redox-dependent adaptive and maladaptive responses of diaphragm muscle to CSH with relevance to respiratory muscle performance.…”

Efectos Morfológicos y Mecánicos en Ratas Sprague Dawley Sometidas a Ciclos de Hipoxia

“…Frente a esta situación, existe un mecanismo fisiológico denominado vasoconstricción pulmonar hipóxica, el cual restringe el flujo sanguíneo a los alvéolos menos oxigenados y lo redirige hacia los mejor oxigenados. Sin embargo, cuando esta respuesta se mantiene por un largo tiempo genera cambios morfofuncionales, dentro de los que destacan un aumento de la vascularización pulmonar y en ocasiones una disminución del número de alvéolos (Urrutia & Aragonés, 2018 fisiológicos y/o fisiopatológicos, con el propósito de mantener la homeostasis respiratoria (Lewis & O'Halloran, 2016). Considerando que el diafragma está sometido a cargas cíclicas producidas por la respiración, es relevante estudiar el efecto de los ciclos de hipoxia en él.…”