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• W2952548013 abstract "Amyotrophic lateral sclerosis (ALS) is the most common disease of motor neurons (MNs) and involves the death of neurons within the motor cortex, brainstem and spinal cord. Within these regions, specific neurons are vulnerable, namely the corticospinal neurons and the larger MNs that comprise fast fatigue-intermediate and fast fatigable (FInt and FF, respectively) motor units (Hegedus et al. 2008, Dukkipati et al. 2018). Slow and fast fatigue-resistant motor units (S and FR, respectively) are relatively resilient. These losses are clinically manifest as a progressive atrophy and weakness of skeletal muscle, eventuating in death from respiratory complications within ∼2–3 years from diagnosis. One of the (many) unanswered questions in the field regards the extent to which skeletal muscle fibres contribute to weakness in ALS. In their recent publication in The Journal of Physiology, Cheng and colleagues used the SOD1G93A (high copy number of the mutant superoxide dismutase 1 with glycine 93 changed to alanine) mouse model of ALS to address this issue (Cheng et al. 2019). They assessed: (i) how much any intrinsic skeletal muscle contractility deficits contributed to weakness in ALS; (ii) the contribution of altered Ca2+ handling of skeletal muscle to weakness in ALS; and (iii) whether any deficits were evident under stressful metabolic conditions (e.g. fatigue) (Cheng et al. 2019). Wild-type (WT) controls and SOD1G93A mice were compared at two well-defined disease stages, pre-symptomatic (P50) and symptomatic (P120–150). It is important to note that vulnerable neurons (corticospinal neurons, FInt and FF MNs and neuromuscular junctions of these MNs) from pre-symptomatic mice exhibit marked degenerative phenotypes well before frank neuronal loss. Additionally, some studies have reported appreciable MN loss in discrete MN pools (e.g. those innervating the tibialis anterior) by P30. Thus, while clinical symptoms may not be observable at P50, MN pathology and denervation may already be apparent. To validate MN loss in flexor digitorum brevis (FDB) motor units, retrograde labelling of MNs with cholera toxin B showed a 67% reduction in FDB MNs of SOD1G93A mice in the symptomatic age group. Although the authors did not report the sizes of the remaining MNs, recent work in the SOD1G93A mouse suggests that the larger MNs from type FInt and FF units are vulnerable, and the remaining surviving MNs are from S and FR units (Dukkipati et al. 2018). Skeletal muscle function was assessed in both whole muscle and single fibre experiments. In whole muscle, there was no impairment of FDB force generation in pre-symptomatic SOD1G93A mice. In symptomatic SOD1G93A mice, significant reductions in muscle force (∼40%) were observed. In whole FDB muscle, there were no alterations in the force normalized for muscle mass, nor in the expression of myosin heavy chain (MyHC) isoforms. In single FDB fibres, there were no deficits in specific force (force normalized to the cross-sectional area of the single FDB muscle fibre), excitation–contraction coupling (as evidenced by tetanic voltage threshold) or Ca2+ handling (as evidenced by resting and tetanic [Ca2+]i). In general, these remarkable data show that, even in a skeletal muscle where the high expression of fast-type MyHC isoforms would suggest that a substantial number of motor units would be vulnerable to degenerations, single muscle fibres are largely unaffected. These data are consistent with previous reports in patient populations, where overall muscle weakness was observed, without any decline in the specific muscle force of single fibres (see Discussion in Cheng et al. 2019). The authors attribute gross muscle weakness of the FDB to atrophy of muscle mass. In light of the selective loss of MNs in ALS, it would have been informative to have an estimate of fibre type-specific cross-sectional areas. These measurements would have helped illuminate whether or not the resilience of skeletal muscle fibres in ALS is type-specific. In other conditions where denervation of skeletal muscle fibres occurs, such as in old age (Fogarty et al. 2018), there is a selective atrophy of type IIx and/or IIb muscle fibres and a sparing of type I and IIa fibres (Fogarty et al. 2019). In the present study, homogenate preparation showing the expression of MyHCSLOW (referred as MHC I in the study) is negligible compared to MyHC2A and MyHC2B (referred as MHC IIa and IIb, respectively, in the study) precluded this assessment. In general FR motor units comprising type IIa muscle fibres (expressing MyHC2A isoform) are similar to type S motor units and are more resilient to denervation effects than FInt and FF units (Hegedus et al. 2008, Fogarty et al. 2018, 2019). In this respect, preservation of the type IIa fibre cross-sectional area (and the preservation of their contribution to FDB mass) would help to disambiguate the issue of whether or not force reduction due to atrophy of muscle mass was generalized (i.e. apparent in all fibre types) or specific to those selectively vulnerable to denervation effects (i.e. type IIx and/or IIb muscle fibres) (Fogarty et al. 2019). Although single FDB skeletal muscle fibres appeared to be unaffected in symptomatic SOD1G93A mice, Cheng and colleagues (2019) expanded upon this result by assessing metabolic capacity. Fatigue resistance (i.e. reduced maximal force generation over time) of skeletal muscle is highly dependent on the maximum aerobic capacity. Indeed, a major component of fibre-typing of skeletal muscles is their fatigability, with type I and IIa fibres exhibiting minimal fatigue (due to high metabolic capacity) and type IIx and IIb fibres exhibiting higher levels of fatigue (due to lower metabolic capacity) (Fogarty et al. 2019). In their experiments, Cheng and colleagues made the fascinating observation that, far from impaired force production, FDB single skeletal muscle fibres from symptomatic SODG93A mice display improved force generation during fatiguing stimulation protocols. Furthermore, in fibres from symptomatic SOD1G93A mice, Ca2+ handling was improved compared to controls. This remarkable degree of plasticity in skeletal muscle fibres was related to enhanced mitochondrial biogenesis (as evidenced by the increased expression of myoglobin and mitochondrial electron transport chain complexes) in FDB fibres from symptomatic SOD1G93A mice, a result entirely consistent with enhanced preservation of muscle force during fatiguing stimulations. In the absence of any MyHC expression change, Cheng and colleagues (2019) interpreted their data in the context of changing fibre type proportions. As outlined above, a more nuanced relationship between mitochondrial capacity for adaptation and fibre type, rather than wholesale fibre type conversion, may underlie these phenomena. Regardless, the observations of improved fatigue resistance and increased mitochondrial biogenesis in SOD1G93A skeletal muscle are valuable contributions to the literature and ought to inform future studies in this area. Although beyond the remit of the present study, it will be an important future direction to examine the aerobic capacity and mitochondrial electron transport proteins in models of ALS that are not potentially confounded by the association of the SOD1 mutation with reactive oxidants and mitochondria. The models that have robust findings of MN loss and a denervation effect include TDP-43, VCP and Wobbler mice (amongst others). Importantly, untangling whether or not mitophagy (Mul1 and Bnip3 were upregulated in SOD1G93A mice compared to controls; Cheng et al. 2019) is exclusive to denervated fibres or prevalent in all skeletal muscle fibres will aid in our understanding of how large a role mitochondrial dysfunction plays in muscle wasting in ALS. This timely study into the physiological consequences of MN loss in ALS is a welcome addition to the field. In particular, the meticulous single fibre functional assessments underscore the relative resilience and compensation of skeletal muscle intrinsic properties in ALS. Despite some particulars regarding the fibre type-specific nature of muscle atrophy in ALS remaining unknown, the evidence that Cheng and colleagues have presented is strongly suggestive that skeletal muscle fibres are an ideal substrate for re-innervation. Indeed, in some respects single FDB muscle fibres from SOD1G93A mice had improved force generation capacity! This is entirely consistent with previous observations showing that strategies targeting the re-innervation of skeletal muscle fibres by the remaining motor axons (e.g. ephrin type A receptor 4 inhibition (Epha4 knockdown) insulin-like growth factor 2 delivery) prolongs survival in ALS rodent models (Van Hoecke et al. 2012; Allodi et al. 2016). Sadly, until we can find reliable ways to improve the health of the vulnerable corticospinal neurons and MNs in ALS, skeletal muscle fibres are destined to remain the strong link in a weakened neuromotor chain. No conflicts, neither real nor perceived exist in regards to this work. Sole author. The NHMRC has funded a C. J. Martin Early Career Fellowship to the author." @default.
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• W2952548013 date "2019-07-08" @default.
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• W2952548013 title "Strong links in a weak chain: skeletal muscle fibres in amyotrophic lateral sclerosis" @default.
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