Question

3. Researchers have been successful in genetically engineering mice by inserting a hyperactive form of a mouse gene (PGC-1B) into growing embryos. They observed that a muscle fiber called IIX became more abundant in PGC-1B hyperactive mice. They also observed that PGC-1B hyperactive mice were capable of running for longer stretches of time (average 33 minutes) than control mice that were not altered (26 minutes).

3a. Based on your knowledge of muscle fiber composition (i.e. slow-twitch, fast-twitch), propose an explanation for how PGC-1B hyperactivity and fiber IIX overproduction might lead to the observed phenotype during the exercise test [4 pts]

3b. Imagine that researchers could monitor muscle activity in the PGC-1B hyperactive mice versus the controls during the functional running test. Which animal muscle tissue (hyperactive or control) do you think would undergo more oxidative phosphorylation during the test? Explain. [4 pts]

3c. Manipulating the type of fibers present in human muscle could help treat muscle-wasting diseases such as muscular dystrophy. Experiments have shown that slow-twitch fibers may be more resistant to wasting. Based on this information, do you think PGC-1B treatment would increase or decrease symptoms of muscular dystrophy in a mouse model of the disease? [3 pts]

Answer 1

Muscle fibres have different properties with respect to force, contraction speed, endurance, oxidative/glycolytic capacity etc. Although adult muscle fibres are normally post‐mitotic with little turnover of cells, the physiological properties of the pre‐existing fibres can be changed in the adult animal upon changes in usage such as after exercise. The signal to change is mainly conveyed by alterations in the patterns of nerve‐evoked electrical activity, and is to a large extent due to switches in the expression of genes. Thus, an excitation‐transcription coupling must exist. It is suggested that changes in nerve‐evoked muscle activity lead to a variety of activity correlates such as increases in free intracellular Ca²⁺ levels caused by influx across the cell membrane and/or release from the sarcoplasmatic reticulum, concentrations of metabolites such as lipids and ADP, hypoxia and mechanical stress. Such correlates are detected by sensors such as protein kinase C (PKC), calmodulin, AMP‐activated kinase (AMPK), peroxisome proliferator‐activated receptor δ (PPARδ), and oxygen dependent prolyl hydroxylases that trigger intracellular signaling cascades. These complex cascades involve several transcription factors such as nuclear factor of activated T‐cells (NFAT), myocyte enhancer factor 2 (MEF2), myogenic differentiation factor (myoD), myogenin, PPARδ, and sine oculis homeobox 1/eyes absent 1 (Six1/Eya1). These factors might act indirectly by inducing gene products that act back on the cascade, or as ultimate transcription factors binding to and transactivating/repressing genes for the fast and slow isoforms of various contractile proteins and of metabolic enzymes. The determination of size and force is even more complex as this involves not only intracellular signaling within the muscle fibres, but also muscle stem cells called satellite cells. Intercellular signaling substances such as myostatin and insulin‐like growth factor 1 (IGF‐1) seem to act in a paracrine fashion. Induction of hypertrophy is accompanied by the satellite cells fusing to myofibres and thereby increasing the capacity for protein synthesis. These extra nuclei seem to remain part of the fibre even during subsequent atrophy as a form of muscle memory facilitating retraining. In addition to changes in myonuclear number during hypertrophy, changes in muscle fibre size seem to be caused by alterations in transcription, translation (per nucleus) and protein degradation.

The physiological properties (shortening velocity, twitch duration, endurance, etc.) that are linked in a fibre type are related to highly different molecular families (MyHC, SERCA, metabolic enzymes, etc.).