Epigenetic imprinting of human skeletal muscle cells: From metabolic diseases to myopathy.

Abstract

Idiopathic inflammatory myopathies (IIM) are a group of rare, heterogeneous, acquired disorders characterized by muscle weakness, excessive muscle fatigue and poor aerobic fitness. They have been historically considered as autoimmune diseases and classified as dermatomyositis, polymyositis or inclusion body myositis (Gazeley & Cronin, 2011). Myositis-specific antibodies define subsets of patients with different responses to treatment and prognosis. IIM primarily affects skeletal muscles and is characterized by chronic inflammation and immune cell infiltration causing muscle damage and excessive fatigability. The primary line of treatment is corticosteroids with the addition of other immunosuppressive therapies in severe or refractory disease (Gazeley & Cronin, 2011). However, the suppression of inflammation with glucocorticoids does not always lead to clinical improvement. There is still a great need to find more effective and less toxic therapies. In this issue of The Journal of Physiology, Nemec et al. (2021) show that 6 months’ supervised training improves muscle functional capacity and the clinical state of IIM patients. Training included 1 h per week of activities of daily living and 1 h of strength training with three series of 10–15 repetitions at 50–70% of 1 repetition maximum. Adherence and compliance to the exercise training programme were excellent with 100% completers. Training improved functional index-2, a valid and reliable index of muscle function in IIM patients, by nearly 40%. The main aim of this study was to investigate disease-related metabolic disturbances in skeletal muscle cells of IIM patients before and after exercise training. Primary culture of human skeletal muscle cells from CD56-positive satellite cells differentiated into metabolically responsive myotubes has been widely used to investigate metabolic and signalling pathways as well as for mechanistic studies to gain insight into cause–effect relationship (Bourlier et al. 2013). Nemec et al. herein observed a defect of total palmitate oxidation rate in myotubes derived from IIM patients chronically treated with palmitate for 3 days to mimic lipid overload in muscle. This metabolic trait has been previously observed in myotubes derived from obese and type 2 diabetic donors and could have interesting clinical implication for IIM patients. They next observed a training-induced up-regulation of lipid oxidative capacity, i.e. measured by elevated palmitate oxidation rate, in primary myotubes of IIM patients cultured before and at the end of the 6 months’ training programme (Nemec et al. 2021). This finding agrees with previous studies showing that training-induced metabolic adaptations are retained in vitro in cultured human myotubes (Bourlier et al. 2013). Interestingly, chronic palmitate treatment for 3 days revealed training-induced molecular changes of lipid metabolism proteins such as mitochondrial respiratory complex proteins, 5′-AMP protein kinase and adipose triglyceride lipase. These molecular changes were overall consistent with the metabolic phenotype of the myotubes. In line with previous studies, Nemec et al. (2021) here observed that in vitro metabolic phenotypes mirrored the clinical characteristics of the donors. Some correlations between in vitro metabolic responses and clinical phenotype were consistent with current knowledge, particularly a tight negative relationship between lipid oxidative capacity in myotubes and total fat mass. Of note, while the study groups were overall well matched, the sample size of the study was low (n = 7, including five female and two male), and two IIM patients were obese, which could confound the findings. A prominent feature of IIM patients is systemic insulin resistance. In the study of Nemec et al., regular exercise for 6 months tended to improve systemic insulin sensitivity based on HOMA-IR and fasting blood glucose. Previous reports have shown that human primary skeletal muscle cells retain the insulin resistant ‘diabetic’ phenotype in vitro (Kase et al. 2015). Thus it is unclear if insulin resistance in IIM patients is a primary factor of the disease intrinsically retained in skeletal muscle cells or rather the consequence of systemic changes such as chronic inflammation and glucocorticoid therapy. It would be therefore interesting to investigate whether the ‘diabetic’ phenotype of IIM patients is retained in the Petri dish and whether exercise training-mediated improvement of insulin sensitivity is conserved in cultured myotubes. The consistent and reproducible observation that environmental changes are intrinsically acquired in human primary skeletal muscle cells indicates that systemic factors can remodel the epigenome of satellite cells to transmit stable changes in cellular phenotypes (Rasmussen et al. 2014). These epigenetic factors include DNA CpG methylation, histone modifications and non-coding RNAs, and are emerging as potential biomarkers that could predict the response to exercise training. Epigenetic modifications participate in transcriptional activation by allowing the recruitment of the transcription machinery to gene promoters. A number of recent studies identified various epigenetic marks in skeletal muscle in response to exercise, particularly DNA methylation of genes known to be differentially expressed after exercise and myomiRs (Rasmussen et al. 2014). Up to now, it is still unclear by which epigenetic factors acquired in vitro cellular phenotypes are triggered. The spectrum of epigenetic regulatory mechanisms may largely depend on disease background and modalities of intervention in longitudinal studies. Future studies should investigate how the metabolic ‘memory’ is imprinted in human primary skeletal muscle cells and how stable this is over time. Altogether, this study lines up with previous reports to show the safety and efficacy of exercise training as a therapeutic option in patients with IIM. This study shows that metabolic dysfunction in cultured myotubes from IIM patients can be partly restored by exercise training. Future studies should examine whether