We previously reported that muscle cells could reprogram into progenitors after traumatic injuries. These injury-induced muscle stem cells (iMuSCs) have increased migration and differentiation capacities, including neuronal differentiation. Recent studies in our laboratory suggest that the hypoxia-induced by tissue injury plays an essential role in the reprogramming process of muscle cells. We hypothesize that muscle cells reprogrammed with hypoxia have increased neuronal differentiation potentials and the neuronal differentiation extends into the formation of neuromuscular junction (NMJ)-like structures. In this study, C2C12 myoblasts were cultured under hypoxic conditions and subsequently in neural differentiation media to generate neurospheres, and then with muscle differentiation media to induce NMJ-like structure formation. Hypoxia-induced muscle cells also produced more robust NMJs compared to controls after intramuscular cell transplantation. Our results suggest hypoxia plays a role in the reprogramming of muscle stem cells, which may have the potential to form neuromuscular junctions and ultimately contribute to functional muscle healing.

Metformin is the most commonly prescribed medication to treat diabetes. Emerging evidence suggests that metformin could have off target effects that might help promote healthy muscle aging, but these effects have not been thoroughly studied in glucose tolerant older individuals. The purpose of this study was to investigate the short-term effects of metformin consumption on skeletal muscle mitochondrial bioenergetics in healthy older adults.
We obtained muscle biopsy samples from 16 healthy older adults previously naïve to metformin and treated with metformin (METF; 3F, 5M), or placebo (CON; 3F, 5M), for two weeks using a randomized and blinded study design. Samples were analyzed using high-resolution respirometry, immunofluorescence, and immunoblotting to assess muscle mitochondrial bioenergetics, satellite cell (SC) content, and associated protein markers.
We found that metformin treatment did not alter maximal mitochondrial respiration rates in muscle compared to CON. In contrast, mitochondrial H2O2 emission and production were elevated in muscle samples from METF versus CON (METF emission: 2.59 ± 0.72 SE Fold, P = 0.04; METF production: 2.29 ± 0.53 SE Fold, P = 0.02). Furthermore, the change in H2O2 emission was positively correlated with the change in type 1 myofiber SC content and this was biased in METF participants (Pooled: R2 = 0.5816, P = 0.0006; METF: R2 = 0.674, P = 0.0125).
These findings suggest that acute exposure to metformin does not impact mitochondrial respiration in aged, glucose-tolerant muscle, but rather, influences mitochondrial-free radical and SC dynamics.
NCT03107884, clinicaltrials.gov.

Muscle stem cells (MuSCs) are essential for muscle growth, maintenance and repair. Over the past decade, experiments in Drosophila have been instrumental in understanding the molecular and cellular mechanisms regulating MuSCs (also known as adult muscle precursors, AMPs) during development. A large number of genetic tools available in fruit flies provides an ideal framework to address new questions which could not be addressed with other model organisms. This review reports the main findings revealed by the study of Drosophila AMPs, with a specific focus on how AMPs are specified and properly positioned, how they acquire their identity and which are the environmental cues controlling their behavior and fate. The review also describes the recent identification of the Drosophila adult MuSCs that have similar characteristics to vertebrates MuSCs. Integration of the different levels of MuSCs analysis in flies is likely to provide new fundamental knowledge in muscle stem cell biology largely applicable to other systems.

BACKGROUND: Muscle satellite cells (SCs) are crucial for muscle regeneration following muscle trauma. Acute skeletal muscle damage results in inflammation and the production of reactive oxygen species (ROS) which may be implicated in SCs activation. Protection of these cells from oxidative damage is essential to ensure sufficient muscle regeneration. The aim of this study is to determine whether SCs activity under conditions of aseptic skeletal muscle trauma induced by exercise is redox-dependent.
METHODS: Based on the SCs content in their vastus lateralis skeletal muscle, participants will be classified as either high or low respondents. In a randomized, double-blind, crossover, repeated-measures design, participants will then receive either placebo or N-acetylcysteine (alters redox potential in muscle) during a preliminary 7-day loading phase, and for eight consecutive days following a single bout of intense muscle-damaging exercise. In both trials, blood samples and muscle biopsies will be collected, and muscle performance and soreness will be measured at baseline, pre-exercise, 2 and 8 days post exercise. Biological samples will be analyzed for redox status and SCs activity. Between trials, a 4-week washout period will be implemented.
CONCLUSIONS: This study is designed to investigate the impact of redox status on SCs mobilization and thus skeletal muscle potential for regeneration under conditions of aseptic inflammation induced by exercise. Findings of this trial should provide insight into (1) molecular pathways involved in SCs recruitment and muscle healing under conditions of aseptic skeletal muscle trauma present in numerous catabolic conditions and (2) whether skeletal muscle\'s potential for regeneration depends on its basal SCs content.
BACKGROUND: ClinicalTrials.gov, ID: NCT03711838 . Registered on 19 Oct 2018.