Skeletal muscle microalterations in patients carrying Malignant Hyperthermia-related mutations of the e-c coupling machinery

Abstract

We have compared the ultrastructure of skeletal muscle biopsies from patients that have survived a [Malignant Hyperthermia, MH] episode and siblings that test positive for MH susceptibility with those from siblings that tested negatives. The aim is to establish whether life long exposure to the MH-related mutation effects may result in subtle abnormalities even in the absence of active episodes and/or clinically detectable deficiencies. Although a specific ultrastructural signature for MH mutants cannot be demonstrated, an MH related pattern of minor alterations does exist. These include the tendency for micro damage to the contractile apparatus and a higher than normal level of mitochondrial abnormalities.

Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals

“…Increased ROS production has been observed in MH RYR1 knock-in mice 11 and it is possible that this may translate into human MHS muscle. Increased ROS production, which can cause DNA damage and structural damage to organelles, could explain the mitochondrial swelling seen in previous electron microscopic studies 10,16,18 . Ca 2+ is also a positive regulator of the mitochondrial permeability transition pore (MPTP) of the inner mitochondrial membrane 32 .…”

“…The CI+CII(OXPHOS) and CII(ETS) FCRs were significantly lower in MHS samples compared to MHN which implies that there is uncoupling of mitochondria in MHS muscle in addition to complex II deficiency, both of which would likely result in inefficient ATP production. The uncoupling of MHS mitochondria is perhaps a side effect of the swelling and structural abnormalities seen in previous human studies 18 or it may be a consequence of chronically elevated myoplasmic calcium concentration in MHS muscle (see below). Since no significant differences in CI(OXPHOS) were found, complex II deficiency seems to be the primary cause for the reduced maximum OXPHOS capacity of MHS muscle as defined by CI+CII(OXPHOS) FCR.…”

“…On a structural level, mitochondrial deformity -an indication of damage -has been observed in multiple reports using electron microscopy. These reports often denote a loss of cristae organization and mitochondrial swelling which suggests there may be metabolic dysfunction and altered OXPHOS in muscles from both MH susceptible mice 10,16 and humans 17,18 .…”

“…In contrast to animal models, research on human MH mitochondrial function is lacking. Despite the structural abnormalities seen in MH susceptible humans 17,18 , evidence for the existence of functional defects is conflicting. Some reports suggest normal OXPHOS and respiratory control in mitochondria of MH susceptible humans 19 , whilst others have claimed impaired OXPHOS and ATP production after bouts of training in MH susceptible individuals 20 .…”

Elongated Mitochondria Constrictions and fission in muscle fatigue

“…For example, even an acute exercise of short duration may affect specific intermitochondrial connections modulated by their surface membrane (Picard et al, 2013), and fragmentation can be induced by cardiac exercise (Coronado et al, 2018). Long-range effects occur in myopathies affecting calcium homeostasis, such as central core disease and malignant hyperthermia in which mitochondrial morphology, distribution and fragmentation are strongly affected (Boncompagni et al, 2009b;Lavorato et al, 2016). Prolonged unbalanced Ca 2+ homeostasis in the myocardium activates the fission process, resulting in increased frequency of mitochondrial profiles due to fragmentation, while also inducing prolonged nanotunneling extensions in the usually structurally conservative cardiac mitochondria (Lavorato et al, 2015(Lavorato et al, , 2017.…”