Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

Abstract

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.

Reduction in Ventilation-Induced Diaphragmatic Mitochondrial Injury through Hypoxia-Inducible Factor 1α in a Murine Endotoxemia Model

“…Furthermore, HIF-1α can be stabilized under normoxic conditions during inflammation, and this activation is associated with drastic levels of proinflammatory cytokines and a decrease in cellular oxygen consumption [39]. LPS, cyclic stretching due to MV, or mitochondrial DNA can block SDH activity and facilitate succinate production, resulting in the inhibition of PHD2, suppression of both polyubiquitination and proteasomal degradation, and promotion of HIF-1α stabilization in vitro and in vivo [1,3,13,16,40]. Peyssonnaux et al reported that HIF-1α activates numerous pivotal proinflammatory cytokines participating in the pathogenesis of LPS-induced sepsis and that HIF-1α inhibition is a defense mechanism against LPS-induced sepsis and mortality [41].…”

“…Mechanical ventilation (MV) is often lifesaving for patients with sepsis-related multiple organ failure. However, prolonged MV can contribute to ventilator-induced diaphragm dysfunction (VIDD), which is characterized by diaphragmatic inactivity and the rapid decline of diaphragm muscle endurance and contractility [1][2][3][4][5][6][7][8]. Sepsis-mediated profound inflammation may provoke diaphragm stretch-related injuries through the enhancement of sarcolemma membrane fragility and aggravate defects in the essential steps of the muscular respiration energy supply chain [9,10].…”

Molecular Fingerprint of BMD Patients Lacking a Portion in the Rod Domain of Dystrophin

“…While in normoxia a knockout of HIF1A/HIF2A did not affect muscle stem cell function, oxygen level < 1% decreased self-renewal and increased differentiation of myoblasts, without effects on cell proliferation [ 40 ]. Hypoxia and dysmetabolism are features of muscular dystrophy due either to the genetic defect itself, respiratory insufficiency, or muscle blood vessel abnormalities [ 41 ]. Thus, its activation in BMD2 patients could be ascribed to the capacity of their muscles to overcome hypoxia by promoting stem cell recruitment.…”

Adolescent Congenital Central Hypoventilation Syndrome: An Easily Overlooked Diagnosis

“…Disregard of the symptoms might lead to serious health consequences, resulting from hypoxia, hypercarbia and sleep apnea, such as pulmonary hypertension and RV hypertrophy. It is worth noting that hypoxia-related symptoms might also occur in certain myopathies (due to respiratory muscle weakness), and thus differential diagnosis is often needed [49]. Pre-and posthyperventilation arterial blood gas tests, which were performed in case of our patient, might be utilized.…”