Investigating the reprogramming of the hypertrophic Myostatin null muscle with Estrogen-related receptor gamma; implications for muscle structure and function

Skeletal muscle is a highly compliant organ system that is composed of muscle fibres, nerves, sensory cells, blood vessels and connective tissue. A central concept of skeletal muscle biology is the existence of an inverse relationship between muscle fibre size and its oxidative capacity which has been used to explain why small fibres are oxidative and large fibres glycolytic. However, sturdiness of this relationship is unknown. In order to investigate the rigour of this relationship we made use of a genetic model that enhances oxidative metabolism, mediated by estrogen-related receptor gamma (Errγ) (a constitutively active orphan nuclear receptor belongs to the ERR subfamily), and the hypertrophic background of Myostatin (a member of the Transforming Growth Factor beta (TGF-β) superfamily that is negatively regulating skeletal muscle mass development) null (Mtn‐/‐) mice. We show that superimposition of Errγ on the Mtn‐/‐ background results in hypertrophic muscle that displays a high oxidative capacity (Mtn‐/‐/ErrγTg/+), thus violating the inverse relationship between muscle fibre cross-sectional area and its oxidative capacity. Thereafter, we examined the canonical view that there is a high number of satellite cells (skeletal muscle resident stem cells) in oxidative muscles. Surprisingly, I found that hypertrophic oxidative muscle fibres from Mtn‐/‐/ErrγTg/+ mice showed a deficit in the number of satellite cells. Unexpectedly, the lower population of satellite cells in the hypertrophic oxidative model is not associated with a lower regenerative capacity. We also examined the relationship between muscle fibre phenotype (size and metabolism) and components of its force transducer apparatus that consists of both extracellular matrix (ECM) and dystrophinglycoprotein complex (DGC). Interestingly, I showed that levels of ECM and DGC entities can be influenced by muscle fibre phenotype. Observations of this work firstly, challenge the notion of a constraint between skeletal muscle fiber size and oxidative capacity, secondly, indicate the important role of the microcirculation in the regenerative capacity of a muscle even with low population of satellite cells, and thirdly, show that the metabolic properties of a muscle fibre are a critical factor to regulate the levels of ECM and DGC proteins