Calcium handling in muscle fibres of mice and men: evolutionary adaptation in different species to optimize performance and save energy

Skeletal muscle fibre specialization is a critical step towards the optimization of the contractile performance. Molecular structure and functional parameters differ among muscle fibres to obtain the best response to specific functional demands. This versatile diversity has been developed during phylogenesis and evolution, but further refinement still occurs during ontogenesis and even in adult life as muscle fibres are endowed with a powerful plasticity.

The diversity among muscle fibres, however, has clear borders defined by the consistency between functional parameters and structural features (Schiaffino & Reggiani, 2011). For example, force generation ability must be matched by the strength of the cytoskeleton, the myotendinous connections and the transversal interfibre connections to withstand mechanical stress without damage. Another example is the necessary match between the kinetic properties of calcium-mediated activation, myofibrillar contractile response and metabolic support. Such consistency is required among functional compartments, as well as within each compartment: for example a balance is necessary between the amount of calcium releasable, SERCA activity to take it up and calsequestrin content in order to maintain a low concentration gradient and avoid leakage.

Even restricting the field to skeletal muscles of mammals, we readily discover that the rules of specialization and diversity are similar, but not equal in different species. Thus, the results obtained in the most studied models, the rodent muscles, cannot be directly applied to our understanding of human muscles without caution.

As was observed 60 years ago by A. V. Hill (1950) and supported by a number of more recent studies (see Schiaffino & Reggiani, 2011), bone length and body size set narrow constraints on the functional requirements of skeletal muscles: small animals require much faster muscles than big animals. In addition, several large animal species have a reduced repertoire of fibre types in trunk and limb muscles, lacking the fastest (or 2B) type. Humans fall within this category and their being bipedal adds a further specific requirement to muscle structural and functional composition, since the postural duties are fulfilled by the lower limbs and, within the lower limbs, by ankle plantar flexors and knee extensors. Postural duties imply long lasting and inexpensive contractile activity.

A detailed knowledge of the functional and kinetic properties of calcium control by the sarcoplasmic reticulum (SR) in human fibres has been until now lacking. This may seem surprising in view of the relevance of the amplitude and kinetics of the calcium transients to the force developed and the time course of the contractile response. However, technical and methodological difficulties have postponed such studies until now.

The gap has been filled by two articles recently published in The Journal of Physiology with C. R. Lamboley as first author (Lamboley et al. 2013, 2014). Starting from biopsy samples of vastus lateralis, a knee extensor muscle whose function in postural duties (maintaining an upright position) is intermingled with phasic activity (jumping or kicking, for example), two fibre populations (the one composed of slow fibres expressing myosin heavy chain 1 and the other composed of fast fibres expressing a fast isoform, most likely 2A) were dissected, identified using myosin isoforms as markers, and studied in detail for the SR molecular composition and function.

In agreement with results obtained in rodents, the endogenous total calcium content of human fibres is higher in fast fibres (0.85 mmol (l fibre volume)⁻¹) than in slow fibres (0.76 mmol l⁻¹), with approximately 90% being localized in the SR and releasable with caffeine and low magnesium. The difference is enhanced when SR is maximally loaded (1.79 vs. 1.45 mmol l⁻¹) and, based on the comparison with rodent muscles (Murphy et al. 2009), we can hypothesize that this is in relation to the greater SR volume and calsequestrin content.

The rate of SR Ca²⁺ uptake is higher in fast than in slow fibres, being ∼0.21 and 0.18 mmol (l fibre volume)⁻¹ s^–1, respectively. Importantly, the affinity of the calcium pump is higher in slow fibres in full accordance with a lower myofibrillar activation threshold. Thus in slow fibres, less Ca²⁺ needs to be released from and loaded into the SR to elicit the minimum measurable force.

Such values, while confirming the expected diversity between fast and slow fibres, reveal some very interesting differences between rodent and human muscle fibres. Being free of the powerful cytosolic calcium buffer, parvalbumin, human fibres can activate myofibrils with a much lower amount of calcium (approximately 135–190 μmol l⁻¹ vs. 300–500 μmol l⁻¹). The rate of calcium reuptake is definitely slower in human than in rodent muscle fibres and this is in relation to the above-mentioned diversity in contractile speed among species with different body size. Possibly related to the lower density of calcium pumps or to the lower free calcium gradient is the much lower degree of leakage in human fibres. Calcium leakage implies a continuous re-uptake and ATP expenditure, and for this reason becomes a determinant of basal metabolism and heat production. As expected according to Kleiber's law, basal energy metabolism is much lower in humans than in rodents in relation to their body size (see for discussion Schiaffino & Reggiani, 2011).

The description given by Lamboley and coworkers (2013, 2014) is rich and detailed; still some important and interesting aspects await further work. Among those open issues are the mechanism and the relevance of the higher cytosolic calcium concentration at rest in slow fibres, the specific role of the two calsequestrin isoforms, the contribution of other intraluminal proteins (triadin and junctin for example) and the adaptations to training and disuse.