Excitation-contraction coupling in muscle

Skeletal muscle has a high resting Cl ⁻ permeability

In skeletal muscle, the resting V _m (∼–90 mV) is much more negative than in neurons (∼–70 mV) owing to the relatively high permeability of the sarcolemma to both K ⁺ and Cl ⁻ . Because of the high resting Cl ⁻ permeability, a relatively large stimulus is normally necessary to bring the V _m to mechanical threshold. In some skeletal muscle diseases, loss-of-function mutations in skeletal muscle Cl ⁻ channels drastically reduce the Cl ⁻ permeability of the sarcolemma. As a result, the skeletal muscle AP threshold can be reached more easily and the muscle becomes hyperexcitable ( Box 15.1 ).

A single action potential causes a brief contraction called a twitch

The temporal relationship between the skeletal muscle AP and the force generated by the muscle is illustrated in Fig. 15.2 . The skeletal muscle AP is similar to the nerve axon AP ( Chapter 7 ) in that it is generated by the activity of voltage-gated Na ⁺ and K ⁺ channels. The development of force by the myocyte begins several milliseconds after the AP. The transient contraction produced by a myocyte in response to a single AP is called a twitch . During the twitch, the contractile force rises to a peak in 30 to 50 milliseconds and then declines over the next 50 to 100 milliseconds. The duration of the twitch is approximately 100-fold longer than the duration of the AP.

How does depolarization increase intracellular [Ca ²⁺ ] in skeletal muscle?

In Chapter 14 we learned that an increase in [Ca ²⁺ ] _i activates contraction in all types of muscle cells. Therefore the central question in E-C coupling is, “How does depolarization of the sarcolemma bring about an increase in [Ca ²⁺ ] _i ?” A related, but more subtle, question is, “How does the [Ca ²⁺ ] _i increase fast enough throughout the muscle fiber so that myofibrils deep inside the fiber can contract synchronously with those close to the surface?”

In skeletal muscle, depolarization of the T-tubule membrane is required for excitation-contraction coupling

Is diffusion of a soluble factor from the surface membrane (e.g., Ca ²⁺ ions entering the cell through voltage-gated Ca ²⁺ channels) to the interior of the cell sufficiently fast to explain the rapid activation of skeletal muscle? A molecule would take about a second to diffuse to the center of a 100-μm diameter skeletal muscle cell ( Chapter 2 ). This is much too slow to account for the development of force during a twitch contraction, which begins just a few milliseconds after the AP ( Fig. 15.2 ).

How, then, does the AP in the sarcolemma rapidly activate the myofibrils in the center of the cell? The critical clue was the discovery that “hot spots” distributed over the sarcolemma (later shown to be T-tubule openings) provide a pathway for depolarization to spread from the surface into the interior of the fiber. T-tubules form an intricate network that extends throughout the skeletal muscle cell ( Fig. 15.3 ). Thus the T-tubule lumen is a narrow extension of the extracellular space into the interior of the muscle cell. The T-tubule membrane contains voltage-gated Na ⁺ and K ⁺ channels, and APs from the surface are propagated along the T-tubule membrane into the interior of the cell.

In skeletal muscle, extracellular Ca ²⁺ is not required for contraction

The T-tubule membrane of skeletal muscle contains receptors for the dihydropyridine derivatives that block L-type voltage-gated Ca ²⁺ channels ( Chapter 8 ). Voltage clamp studies in skeletal muscle demonstrate that inward Ca ²⁺ currents are generated by depolarization ( Fig. 15.4 ) and that these currents are blocked by dihydropyridines. Thus the dihydropyridine receptors (DHPRs) in the T-tubule membrane are L-type Ca ²⁺ channels. Therefore we might reasonably expect that the Ca ²⁺ entry through these channels raises [Ca ²⁺ ] _i and activates contraction, but this is not the case. Skeletal muscle continues to contract normally when bathed in a solution containing no Ca ²⁺ ions. This finding indicates that Ca ²⁺ entry is not essential for skeletal muscle contraction and that all the Ca ²⁺ required for activating the contractile machinery is derived from intracellular sources. This is in marked contrast to the mechanism of E-C coupling in cardiac muscle, where Ca ²⁺ entry through voltage-gated Ca ²⁺ channels is required (see later). Even though Ca ²⁺ entry through DHPRs is not required for E-C coupling in skeletal muscle, the DHPRs do play a crucial role in this mechanism.