No matter the type, when it comes to recovery all fibres are similar

A multitude of hormonal and neuronal signals converge to maintain glucose homeostasis in conditions of altered energy balance (e.g. exercise, following a meal). Skeletal muscle is undoubtedly the most important depot/sink for maintaining glucose homeostasis and is responsible for the majority of insulin-stimulated glucose uptake. As such, muscle has been extensively studied as a site for interventions aimed at altering whole-body glucose handling. Adding to the complexity of studying skeletal muscle is the fact that there are numerous fibre types. The two broad categories of fibre type are type I (slow, oxidative) and type II (fast, glycolytic), along with a spectrum of other fibre types expressing characteristics of both type I and type II fibres. Importantly, various fibre types allow for appropriate motor unit recruitment that corresponds to the functional and metabolic demands of the movement being performed. Muscle fibres are also generally considered to be adaptable and may change over time in response to hormonal or neural signals (Albers et al. 2015). It is generally well accepted that type I fibres contain higher expression of GLUT 4, hexokinase and glycogen synthase, while type II fibres typically express higher levels of insulin-signalling proteins, particularly those that have been shown to be responsive to exercise (Albers et al. 2015). This suggests that type I fibres have a higher capacity for glucose transport while type II fibres may have the capacity to elicit a greater response to insulin following exercise (particularly in insulin-resistant states). For many years it has been known that a single bout of exercise can transiently improve skeletal muscle insulin response in humans. However, previous studies examining the effects of a single bout of exercise on insulin response have primarily done so at the whole body or whole muscle level. In rodents, subtle differences exist in both fibre types as well as fibre type response to prior exercise. For instance, Wang et al. (2019) reported increased TBC1D4Ser704 phosphorylation in type I and type II fibres, but not type IIx (a subset of type II fibres) 3.5 h after exercise under insulin-stimulated conditions. However, studies examining the underlying molecular signalling that may potentially distinguish type I and type II fibres from each other during recovery from exercise in human subjects are sparse. Larsen et al. (2020) aimed to address this gap to determine whether following a single bout of exercise, type I and II fibres respond differently with regards to insulin sensitivity and phosphorylation events of key proteins involved in insulin signalling and glucose metabolism. In order to delineate these potential effects, Larsen et al. (2020) employed a one-legged knee-extensor protocol at 80% of peak workload followed by a euglycaemic hyperinsulinaemic clamp (EHC) in nine healthy men. Two biopsies from the vastus lateralis muscle were taken; the first 4 h post-exercise and immediately before the two-hour EHC, and the second immediately following the EHC. A corresponding biopsy from the contralateral muscle served as a control at each time point. Single fibres were dissected and fibre type was determined using dot blotting, allowing for the determination of fibre type via immunoblotting by probing samples against myosin heavy chain (MHC) antibodies (MHC I or II). Following exercise, glycogen content was equally reduced in both fibre types, serving as confirmation that the exercise protocol was sufficient to recruit both type I and type II fibres equally. Additionally, Type II fibres exhibited significantly higher protein expression of both Akt2, TBC1D1 and TBC1D4 (insulin signalling), while type I fibres exhibited higher levels of GS. These results are consistent with the literature, confirming the efficacy of their fibre isolation methodology. These fibre differences were carefully considered when examining phosphorylation events and results were normalized to total protein content wherever possible. The primary findings by Larsen et al. (2020) showed that during recovery, 4 h after a single acute bout of dynamic knee-extensor exercise: (1) signalling at the level of TBC1D4 and TBC1D1 is similar irrespective of fibre type following a 2 h euglycaemic clamp; and (2) potentiation of insulin-induced increases in glycogen synthase activity are also similar in both fibre types. These results demonstrate that that both type I and type II fibres likely play a similar role in regulating glycogen resynthesis in normal physiological conditions, i.e. normal blood glucose. Both TBC1D1 and TBC1D4 have been regulatory proteins of interest with regards to both insulin-stimulated and contraction-mediated glucose uptake in skeletal muscle. As mentioned by the authors, phosphorylation of TBC1D4Ser704 is often regarded as a key regulatory site for contraction-mediated signalling and recent work has implicated this regulatory site of TBC1D4 with the AMPK signalling axis. Importantly, type II fibres typically express higher levels of TBC1D4, suggesting that these fibres have a higher capacity to respond to contraction-mediated activation of insulin signalling (e.g. AMPK activation, and subsequent phosphorylation of TBC1D4) during recovery from exercise. Although no specific fibre-type differences were observed in this study with regards to TBC1D4 phosphorylation following insulin infusion, there are several important results that offer insight into the importance of TBC1D4 signalling. The results pertaining to TBC1D4Ser704 are of particular interest as previous studies have suggested fibre type-specific regulation at this residue following exercise with type II fibres showing significantly increased phosphorylation compared with type I, despite no differences in glycogen depletion (Kristensen et al. 2015). Interestingly, these fibre type-specific effects were not shown in the current study, although TBC1D4Ser704 phosphorylation persisted and was significantly higher after exercise than any other residue. Thus, it is plausible that TBC1D4Ser704 may play an additional important role in recovery from exercise outside of direct insulin signalling, although this remains to be determined. The authors speculated that this phosphorylation likely persisted due to prolonged increases in AMPK activation following exercise and may play a role in influencing any post-translational modifications (outside of phosphorylation) of TBC1D4 potentially influencing cellular localization and activity during recovery from exercise. This study provides an important working model for understanding how muscle fibre types respond to acute exercise. The authors acknowledge that despite both fibre types responding similarly during recovery from a single bout of exercise with respect to insulin-induced phosphor-regulation and glycogen resynthesis, it is possible that under conditions of hyperglycaemia (e.g. T2D) fibre type-specific deficits in glucose handling may manifest. A plethora of existing research supports the notion that in conditions of prolonged metabolic dysregulation in humans, muscles often undergo a phenotypic shift away from type I fibres and towards type II fibres and this shift is associated with the typically observed impairments in glucose tolerance (Albers et al. 2015). However, Albers et al. (2015) have also reported that phosphor-regulation of TBC1D4 and TBC1D1 in type II fibres exposed to insulin remained similar in both T2D and lean healthy individuals. Thus, since type II fibres display a higher capacity for phosphor-regulation than type I, it is plausible that these fibres may be more responsive to acute exercise-induced restorations in insulin signalling in insulin-resistant states (e.g. T2D). Whether this increased phosphor-regulation of type II fibres is sufficient to maintain similar levels of insulin-stimulated glucose uptake following exercise in these states remains to be seen. Thus, a limitation in this study was the lack of a functional readout for glucose uptake, as acknowledged by the authors. Moving forward, examining whether potential impairments in glucose uptake in type II fibres in insulin-resistant states are attenuated during recovery from prior exercise is warranted. In rodents, Pataky et al. (2019) demonstrated fibre type-specific effects in insulin-resistant rats showing that only type II fibres were insulin resistant following two weeks of a high fat diet and that this impairment was attenuated immediately after exercise in all type II fibres while improved glucose uptake persisted in type II fibres 3 h post-exercise. Thus, the regulation of type II fibres may play an increasingly important role as the content of type I fibres declines. Irrespective of a functional readout, Larsen et al. (2020) have provided valuable insight into the molecular signalling events in both type I and type II fibres in relation to improved glucose uptake immediately following exercise, and have provided a sound working model for examining the fibre type-specific effects of an acute bout of exercise in lean healthy individuals. Whether or not these relationships hold true in conditions of metabolic impairment remains to be seen. In conclusion, in healthy individuals under euglycaemic conditions, a prior bout of exercise has similar effects on both type I and type II muscle fibres with regards to phosphor-regulation of TBC1D4, TBC1D1 and GS activity. Studies examining the functional capacity for fibre type-specific glucose uptake in hyperglycaemic conditions are warranted. No competing interests declared. Sole author. No funding received for this manuscript-Journal Club Submission. A.J.L. is funded by an Ontario Graduate Scholarship.

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