Current research shows a clear correlation between strong mitochondrial capacity, healthy
muscle and general public health. A sedentary lifestyle increases the risk of a whole host of
so called ‘western diseases’, while an active lifestyle reduce the risk of said diseases. Thus,
well-functioning muscles are a necessity for general health. So far endurance exercise is the
most effective method to improve muscle function. This thesis will focus on the cellular
mechanisms that regulate muscle performance and how these can be improved.
In the first study, we show that supplemented dietary nitrate enhances Ca2+ handling and
submaximal force in mouse fast twitch muscle. Continuing this, in study two, we show that
the increased submaximal force enhances voluntary activity in mice, presumably due to a
shifted perceived effort of running. In study three we show that mild stress from cold
exposure can enhance mitochondrial biogenesis resulting in improved fatigue resistance
without exercise. The cold environment seems to induce a sarcoplasmic reticulum (SR) Ca2+
leak in the skeletal muscle. In study four we investigated why short (180s) high intensity
interval training works better for enhancing endurance than regular low-intensity exercise.
We show that oxidants formed during exercise causes ryanodine receptor modifications,
which result in a SR Ca2+ leak and this in turn likely triggers transcription to improved
mitochondrial capacity. In study five we show that inducing a mild SR Ca2+ leak, either with
exercise or pharmacological tools, drive mitochondrial biogenesis. In study six we show that
a in a model of ageing, a degenerative mitochondrial problem causes myopathy via reduced
SR Ca2+ release.
Ca2+ is a central player in muscle function. This thesis shows that diet, exercise and age have
the ability to affect skeletal muscle Ca2+ handling. Most importantly, Ca2+ signals can
improve mitochondrial function, resulting in improved muscle function. However
degenerative mitochondria causes reduced Ca2+handling that leads to muscle weakness. This
is one of the reasons an active lifestyle is so important for the elderly, because it improves the
mitochondrial function rather than being degraded. Perhaps in the future, inducing a small SR
Ca2+ leak could minimize some of the risks associated with sedentary lifestyle
