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.
Highlights
Muscular dystrophies (MDs) are a heterogeneous group of inherited degenerative muscle disorders resulting in progressive muscle weakness and dystrophic histopathology observed on muscle biopsies
Hypoxia and Hypoxia-Inducible Factor 1 α (HIF-1α) signaling alterations clearly influence skeletal muscle structure, metabolism, regeneration and function. Both conditions occur in MDs due either to the genetic defect itself or to a resulting respiratory insufficiency or muscle blood vessel abnormalities
We can hypothesize that on one hand, hypoxia and MD-associated muscle disturbances themselves may have synergistic effects on key converging processes namely oxidative stress, metabolism and regeneration, initiating a vicious circle whose deleterious consequences could participate in pathophysiological mechanisms underlying muscle weakness in a significant number of patients with MDs (Figure 6)
Summary
Muscular dystrophies (MDs) are a heterogeneous group of inherited degenerative muscle disorders resulting in progressive muscle weakness and dystrophic histopathology observed on muscle biopsies. The impact of hypoxia on muscle pathophysiology remains poorly documented [4] This is surprising since several MDs are known to cause chronic hypoxemia due to hypoventilation as a consequence of respiratory muscle weakness. ((11)) TThhee mmaaiinn ccaauussee ooff lluunngg ffaaiilluurree iiss rreeccuurrrreennttppnneeuummoonniiaauussuuaallllyysseeccoonnddaarryyttoo ccoouugghh iinneefffificciieennccyyoorrcchhrroonniiccaassppiirraattiioonn.. Respiratory muscle contraction generates a change in airway pressure allowing the movement of air through an open airway, increasing or decreasing lung volume depending on the activated muscles. The reduction of muscle tone affects inspiratory muscles While this reduction has a limited effect in normal subject, in MDs with muscle weakness and decreased compliance of the respiratory system, it induces a reduction of the tidal volume, contributing to nocturnal hypoventilation. SRBDs were reported in DM, even in the absence of typical OSAS symptoms such as excessive daytime sleepiness, highlighting the need of a polysomnographic evaluation in those patients [51]
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