Diseased muscles that lack dystrophin or laminin-α2 have altered compositions and proliferation of mononuclear cell populations

BACKGROUND: Multiple types of mononucleate cells reside among the multinucleate myofibers in skeletal muscles and these mononucleate cells function in muscle maintenance and repair. How neuromuscular disease might affect different types of muscle mononucleate cells had not been determined. In this study, therefore, we examined how two neuromuscular diseases, dystrophin-deficiency and laminin-α2-deficiency, altered the proliferation and composition of different subsets of muscle-derived mononucleate cells. METHODS: We used fluorescence-activated cell sorting combined with bromodeoxyuridine labeling to examine proliferation rates and compositions of mononuclear cells in diseased and healthy mouse skeletal muscle. We prepared mononucleate cells from muscles of mdx (dystrophin-deficient) or Lama2(-/- )(laminin-α2-deficient) mice and compared them to cells from healthy control muscles. We enumerated subsets of resident muscle cells based on Sca-1 and CD45 expression patterns and determined the proliferation of each cell subset in vivo by BrdU incorporation. RESULTS: We found that the proliferation and composition of the mononucleate cells in dystrophin-deficient and laminin-α2-deficient diseased muscles are different than in healthy muscle. The mdx and Lama2(-/- )muscles showed similar significant increases in CD45(+ )cells compared to healthy muscle. Changes in proliferation, however, differed between the two diseases with proliferation increased in mdx and decreased in Lama2(-/- )muscles compared to healthy muscles. In particular, the most abundant Sca-1(-)/CD45(- )subset, which contains muscle precursor cells, had increased proliferation in mdx muscle but decreased proliferation in Lama2(-/- )muscles. CONCLUSION: The similar increases in CD45(+ )cells, but opposite changes in proliferation of muscle precursor cells, may underlie aspects of the distinct pathologies in the two diseases

New fundamental resistance exercise determinants of molecular and cellular muscle adaptations

Physical activity relies on muscular force. In adult skeletal muscle, force results from the contraction of postmitotic, multinucleated myofibres of different contractile and metabolic properties. Myofibres can adapt to (patho-)physiological conditions of altered functional demand by radial growth, longitudinal growth, and regulation of fibre type functional gene modules. The adaptation's specificity depends on the distinct molecular and cellular events triggered by unique combinations of conditional cues. In order to derive effective and tailored exercise prescriptions, it must be determined (1) which mechano-biological condition leads to what molecular/cellular response, and (2) how this molecular/cellular response relates to the structural, contractile, and metabolic adaptation. It follows that a thorough mechano-biological description of the loading condition is imperative. Unfortunately, the definition of (resistance) exercise conditions in the past and present literature is insufficient. It is classically limited to load magnitude, number of repetitions and sets, rest in-between sets, number of interventions/week, and training period. In this review, we show why the current description is insufficient, and identify new determinants of quantitative and/or qualitative effects on skeletal muscle with respect to resistance exercise in healthy, adult humans. These new mandatory determinants comprise the fractional and temporal distribution of the contraction modes per repetition, duration of one repetition, rest in-between repetitions, time under tension, muscular failure, range of motion, recovery time, and anatomical definition. We strongly recommend to standardise the design and description of all future resistance exercise investigations by using the herein proposed set of 13 mechano-biological determinants (classical and new ones