Impact of preterm birth on muscle mass and function: a systematic review and meta-analysis.

Individuals born preterm present lower exercise capacity. Along with the cardiopulmonary responses and activity level, muscle strength is a key determinant of exercise capacity. This systematic review aimed to summarize the current knowledge on the impact of preterm birth on skeletal muscle mass and function across the lifespan. The databases PubMed, MEDLINE, EBM, Embase, CINAHL Plus, Global Index Medicus, and Google Scholar were searched using keywords and MeSH terms related to skeletal muscle, preterm birth, and low birth weight. Two independent reviewers undertook study selection, data extraction, and quality appraisal using Covidence review management. Data were pooled to estimate the prematurity effect on muscle mass and function using the R software. From 4378 studies retrieved, 132 were full-text reviewed and 25 met the inclusion/exclusion criteria. Five studies presented a low risk of bias, and 5 had a higher risk of bias due to a lack of adjustment for confounding factors and presenting incomplete outcomes. Meta-analyses of pooled data from homogenous studies indicated a significant reduction in muscle thickness and jump test (muscle power) in individuals born preterm versus full-term with standardized mean difference and confidence interval of - 0.58 (0.27, 0.89) and - 0.45 (0.21, 0.69), respectively.    Conclusion: Overall, this systematic review summarizing the existing literature on the impact of preterm birth on skeletal muscle indicates emerging evidence that individuals born preterm, display alteration in the development of their skeletal muscle mass and function. This work also highlights a clear knowledge gap in understanding the effect of preterm birth on skeletal muscle development. What is Known: • Preterm birth, which occurs at a critical time of skeletal muscle development and maturation, impairs the development of different organs and tissues leading to a higher risk of comorbidities such as cardiovascular diseases. • Preterm birth is associated with reduced exercise capacity. What is New: • Individuals born preterm display alterations in muscle mass and function compared to individuals born at term from infancy to adulthood. • There is a need to develop preventive or curative interventions to improve skeletal muscle health in preterm-born individuals.

Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1.

Muscle stem cells, the engine of muscle repair, are affected in myotonic dystrophy type 1 (DM1); however, the underlying molecular mechanism and the impact on the disease severity are still elusive. Here, we show using patients' samples that muscle stem cells/myoblasts exhibit signs of cellular senescence in vitro and in situ. Single cell RNAseq uncovers a subset of senescent myoblasts expressing high levels of genes related to the senescence-associated secretory phenotype (SASP). We show that the levels of interleukin-6, a prominent SASP cytokine, in the serum of DM1 patients correlate with muscle weakness and functional capacity limitations. Drug screening revealed that the senolytic BCL-XL inhibitor (A1155463) can specifically remove senescent DM1 myoblasts by inducing their apoptosis. Clearance of senescent cells reduced the expression of SASP, which rescued the proliferation and differentiation capacity of DM1 myoblasts in vitro and enhanced their engraftment following transplantation in vivo. Altogether, this study identifies the pathogenic mechanism associated with muscle stem cell defects in DM1 and opens a therapeutic avenue that targets these defective cells to restore myogenesis.

Neonatal hyperoxia leads to white adipose tissue remodeling and susceptibility to hypercaloric diet.

Individuals born preterm are at higher risk of cardiovascular and metabolic diseases in adulthood, through mechanisms not completely understood. White adipose tissue in humans and rodents is a dynamic endocrine organ and a critical player in the regulation of metabolic homeostasis. However, the impact of preterm birth on white adipose tissue remains unknown. Using a well-established rodent model of preterm birth-related conditions in which newborn rats are exposed during postnatal days 3-10 to 80% of oxygen, we evaluated the impact of transient neonatal hyperoxia on adult perirenal white adipose tissue (pWAT) and liver. We further assessed the effect of a second hit with a high-fat high-fructose hypercaloric diet (HFFD). We evaluated 4-month-old adult male rats after 2 months of HFFD. Neonatal hyperoxia led to pWAT fibrosis and macrophage infiltration without modification in body weight, pWAT weight, or adipocyte size. In animals exposed to neonatal hyperoxia vs. room air control, HFFD resulted in adipocyte hypertrophy, lipid accumulation in the liver, and increased circulating triglycerides. Overall, preterm birth-related conditions had long-lasting effects on the composition and morphology of pWAT, along with a higher susceptibility to the deleterious impact of a hypercaloric diet. These changes suggest a developmental pathway to long-term metabolic risk factors observed clinically in adults born preterm through programming of white adipose tissue.

Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies.

Skeletal muscle possesses a high plasticity and a remarkable regenerative capacity that relies mainly on muscle stem cells (MuSCs). Molecular and cellular components of the MuSC niche, such as immune cells, play key roles to coordinate MuSC function and to orchestrate muscle regeneration. An abnormal infiltration of immune cells and/or imbalance of pro- and anti-inflammatory cytokines could lead to MuSC dysfunctions that could have long lasting effects on muscle function. Different genetic variants were shown to cause muscular dystrophies that intrinsically compromise MuSC function and/or disturb their microenvironment leading to impaired muscle regeneration that contributes to disease progression. Alternatively, many acquired myopathies caused by comorbidities (e.g., cardiopulmonary or kidney diseases), chronic inflammation/infection, or side effects of different drugs can also perturb MuSC function and their microenvironment. The goal of this review is to comprehensively summarize the current knowledge on acquired myopathies and their impact on MuSC function. We further describe potential therapeutic strategies to restore MuSC regenerative capacity.

Cardiac Left Ventricle Mitochondrial Dysfunction After Neonatal Exposure to Hyperoxia: Relevance for Cardiomyopathy After Preterm Birth.

BACKGROUND: Individuals born preterm present left ventricle changes and increased risk of cardiac diseases and heart failure. The pathophysiology of heart disease after preterm birth is incompletely understood. Mitochondria dysfunction is a hallmark of cardiomyopathy resulting in heart failure. We hypothesized that neonatal hyperoxia in rats, a recognized model simulating preterm birth conditions and resulting in oxygen-induced cardiomyopathy, induce left ventricle mitochondrial changes in juvenile rats. We also hypothesized that humanin, a mitochondrial-derived peptide, would be reduced in young adults born preterm. METHODS: Sprague-Dawley pups were exposed to room air (controls) or 80% O2 at postnatal days 3 to 10 (oxygen-induced cardiomyopathy). We studied left ventricle mitochondrial changes in 4 weeks old males. In a cohort of young adults born preterm (n=55) and age-matched term (n=54), we compared circulating levels of humanin. RESULTS: Compared with controls, oxygen-exposed rats showed smaller left ventricle mitochondria with disrupted integrity on electron microscopy, decreased oxidative phosphorylation, increased glycolysis markers, and reduced mitochondrial biogenesis and abundance. In oxygen-exposed rats, we observed lipid deposits, increased superoxide production (isolated cardiomyocytes), and reduced Nrf2 gene expression. In the cohort, left ventricle ejection fraction and peak global longitudinal strain were similar between groups however humanin levels were lower in preterm and associated with left ventricle ejection fraction and peak global longitudinal strain. CONCLUSIONS: In conclusion, neonatal hyperoxia impaired left ventricle mitochondrial structure and function in juvenile animals. Serum humanin level was reduced in preterm adults. This study suggests that preterm birth-related conditions entail left ventricle mitochondrial alterations that may underlie cardiac changes perpetuated into adulthood. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03261609.

Transient neonatal exposure to hyperoxia, an experimental model of preterm birth, leads to skeletal muscle atrophy and fiber type switching.

Individuals born preterm show reduced exercise capacity and increased risk for pulmonary and cardiovascular diseases, but the impact of preterm birth on skeletal muscle, an inherently critical part of cardiorespiratory fitness, remains unknown. We evaluated the impacts of preterm birth-related conditions on the development, growth, and function of skeletal muscle using a recognized preclinical rodent model in which newborn rats are exposed to 80% oxygen from days 3 to 10 of life. We analyzed different hindlimb muscles of male and female rats at 10 days (neonatal), 4 weeks (juvenile), and 16 weeks (young adults). Neonatal high oxygen exposure increased the generation of reactive oxygen species (ROS) and the signs of inflammation in skeletal muscles, which was associated with muscle fiber atrophy, fiber type shifting (reduced proportion of type I slow fibers and increased proportion of type IIb fast-fatigable fibers), and impairment in muscle function. These effects were maintained until adulthood. Fast-twitch muscles were more vulnerable to the effects of hyperoxia than slow-twitch muscles. Male rats, which expressed lower antioxidant defenses, were more susceptible than females to oxygen-induced myopathy. Overall, preterm birth-related conditions have long-lasting effects on the composition, morphology, and function of skeletal muscles; and these effects are sex-specific. Oxygen-induced changes in skeletal muscles could contribute to the reduced exercise capacity and to increased risk of diseases of preterm born individuals.