Drug Discovery Opinion

The fibres that make up skeletal muscle broadly fall into two groups: Type I, ‘slow-twitch’ myofibres, and Type II, ‘fast-twitch’ myofibres. Slow-twitch fibres utilise oxidative metabolism for energy generation and are associated with endurance, whilst fast-twitch fibres use a mixture of oxidative and anaerobic metabolism but are quicker to fatigue. Sprinters have up to 80 per cent type II fibres while marathon runners have up to 90 per cent type I fibres. Those that have a more sedentary lifestyle have about the same percentage of both.

Obese individuals have relatively fewer Type I fibres compared to average-weight counterparts and Type I fibres are believed to confer resistance to obesity. Consistent with this, the numbers of Type I fibres decrease in response to inactivity and or a high-fat diet (HFD). Conversely, numbers of Type I fibres increase in response to exercise.

Researchers at Yale University School of Medicine have now identified MAPK phosphatase-1 (MKP-1) as a key player in the Type I/Type II shift in response to HFD. The group had previously shown that mice deficient in MKP-1 displayed increased energy expenditure and were resistant to diet-induced obesity. This new study, published in the Journal of Clinical Investigation, found that MKP-1 was overexpressed in skeletal muscle of mice in response to excess dietary fat.

MKP-1 dephosphorylates, and consequently deactivates, MAP kinases in the nucleus. In the study, MKP-1 overexpression reduced p38 MAPK-mediated phosphorylation of PPARγ coactivator 1α (PGC-1α), which plays a central role in maintaining levels of Type I myofibres. The phosphorylation of PGC-1α is believed to stabilise the protein and, consistent with this, MKP-1 deficient mice had higher levels of PGC-1α in skeletal muscle than did wild-type mice and were refractory to the loss of Type I myofibres when fed a high-fat diet.

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