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Muscle fibers are the largest cells in the body, and one of its few syncytia. Individual cell sizes are variable and adaptable, but what governs cell size has been unclear. We find that muscle fibers are DNA scarce compared to other cells, and that the nuclear number (N) adheres to the relationship N = aVb where V is the cytoplasmic volume. N invariably scales sublinearly to V (b, Muscle fibers are the largest cells in the body and contain less DNA per unit volume than other cells even if they have multiple nuclei. Here, the authors show that the number of nuclei regulates the cell size with similar scaling properties in mice and humans.

Referring to the muscle memory theory, previously trained muscles acquire strength and volume much faster than naive muscles. Using extreme experimental models such as synergist ablation or steroid administration, previous studies have demonstrated that the number of nuclei increases when a muscle becomes enlarged, which serves as a cellular muscle memory mechanism for the muscle. In the present study, we found that, when rats were subjected to physiologically relevant resistance training, the number of myonuclei increased and was retained during a long-term detraining period. The acquired myonuclei were related to a greater degree of muscle hypertrophic and mitochondrial biogenesis processes following subsequent hypertrophic conditions. Our data suggest a cellular mechanism supporting the notion that exposing young muscles to resistance training would help to restore age-related muscle loss coupled with mitochondrial dysfunction in later life.Muscle hypertrophy induced by resistance training is accompanied by an increase in the number of myonuclei. The acquired myonuclei are viewed as a cellular component of muscle memory by which muscle enlargement is promoted during a re-training period. In the present study, we investigated the effect of exercise preconditioning on mitochondrial remodelling induced by resistance training. Sprague-Dawley rats were divided into four groups: untrained control, training, pre-training or re-training. The training groups were subjected to weight loaded-ladder climbing exercise training. Myonuclear numbers were significantly greater (up to 20%) in all trained muscles compared to untrained controls. Muscle mass was significantly higher in the re-training group compared to the training group (∼2-fold increase). Mitochondrial content, mitochondrial biogenesis gene expression levels and mitochondrial DNA copy numbers were significantly higher in re-trained muscles compared to the others. Oxidative myofibres (type I) were significantly increased only in the re-trained muscles. Furthermore, in vitro studies using insulin-like growth factor-1-treated L6 rat myotubes demonstrated that myotubes with a higher myonuclear number confer greater expression levels of both mitochondrial and nuclear genes encoding for constitutive and regulatory mitochondrial proteins, which also showed a greater mitochondrial respiratory function. These data suggest that myonuclei acquired from previous training facilitate mitochondrial biogenesis in response to subsequent retraining by (at least in part) enhancing cross-talk between mitochondria and myonuclei in the pre-conditioned myofibres.

Resistance towards deltamethrin (DMT) in the crustacean ectoparasite Lepeophtheirus salmonis (Caligidae) is a problem on fish farms lining the North Atlantic Ocean. Two Norwegian strains with different susceptibility towards DMT were crossed in the parental generation (P0), females from a sensitive strain were crossed with males from a resistant strain and vice versa. Individual susceptibility towards DMT was assessed in the second filial generation (F2). DMT resistance was only found in F2 descendants when the P0 females were from the resistant strain, pointing to maternal inheritance. Since maternal inheritance might be linked to the mitochondrial (mt) genome, the nucleotide sequences and the gene expressions of mt-genes were analysed. Twenty non-synonymous single nucleotide polymorphisms (SNPs) were identified in mt-transcripts from resistant F2 parasites, including SNPs in two cytochrome C oxidase subunits (COX1 and COX3) and two subunits of the NADH dehydrogenase complex (ND1 and ND5) previously linked to DMT resistance in the salmon louse. Differential expression analysis between the sensitive and resistant strain revealed strain effect in seven out of twelve mt-genes. The current study also show that DNA fragmentation (indicating apoptosis) was affected by DMT exposure in skeletal muscle tissue and that resistant parasites undergo less apoptosis than sensitive parasites.

Vaccination with naked DNA holds great promise but immunogenicity needs to be improved. DNA constructs encoding bivalent proteins that bind antigen-presenting cells (APC) for delivery of antigen have been shown to enhance T and B cell responses and protection in tumour challenge experiments. However, the mechanism for the increased potency remains to be determined. Here we have constructed DNA vaccines that express the fluorescent protein mCherry, a strategy which allowed tracking of vaccine proteins. Transfected muscle fibres in mice were visualized, and their relationship to infiltrating mononuclear cells could be determined. Interestingly, muscle fibers that produced MHC class II-specific dimeric vaccine proteins with mCherry were for weeks surrounded by a localized intense cellular infiltrate composed of CD45+, MHC class II+ and CD11b+ cells. Increasing numbers of eosinophils were observed among the infiltrating cells from day 7 after immunization. The local infiltrate surrounding mCherry+ muscle fibers was dependent on the MHC II-specificity of the vaccine proteins since the control, a non-targeted vaccine protein, failed to induce similar infiltrates. Chemokines measured on day 3 in immunized muscle indicate both a DNA effect and an electroporation effect. No influence of targeting was observed. These results contribute to our understanding for why targeted DNA vaccines have an improved immunogenicity.