During strenuous exercise lactic acid accumulates producing a reduction in muscle pH. In addition, exercise causes a loss of muscle K+ leading to an increased concentration of extracellular K+ ([K+]o). Individually, reduced pH and increased [K+]o have both been suggested to contribute to muscle fatigue. To study the combined effect of these changes on muscle function, isolated rat soleus muscles were incubated at a [K+]o of 11 mm, which reduced tetanic force by 75 %. Subsequent addition of 20 mm lactic acid led, however, to an almost complete force recovery. A similar recovery was observed if pH was reduced by adding propionic acid or increasing the CO2 tension. The recovery of force was associated with a recovery of muscle excitability as assessed from compound action potentials. In contrast, acidification had no effect on the membrane potential or the Ca2+ handling of the muscles. It is concluded that acidification counteracts the depressing effects of elevated [K+]o on muscle excitability and force. Since intense exercise is associated with increased [K+]o, this indicates that, in contrast to the often suggested role for acidosis as a cause of muscle fatigue, acidosis may protect against fatigue. Moreover, it suggests that elevated [K+]o is of less importance for fatigue than indicated by previous studies on isolated muscles.

Generation of the action potentials (AP) necessary to activate skeletal muscle fibers requires that inward membrane currents exceed outward currents and thereby depolarize the fibers to the voltage threshold for AP generation. Excitability therefore depends on both excitatory Na+ currents and inhibitory K+ and Cl− currents. During intensive exercise, active muscle loses K+ and extracellular K+ ([K+]o) increases. Since high [K+]o leads to depolarization and ensuing inactivation of voltage-gated Na+ channels and loss of excitability in isolated muscles, exercise-induced loss of K+ is likely to reduce muscle excitability and thereby contribute to muscle fatigue in vivo. Intensive exercise, however, also leads to muscle acidification, which recently was shown to recover excitability in isolated K+-depressed muscles of the rat. Here we show that in rat soleus muscles at 11 mM K+, the almost complete recovery of compound action potentials and force with muscle acidification (CO2 changed from 5 to 24%) was associated with reduced chloride conductance (1731 ± 151 to 938 ± 64 μS/cm2, P < 0.01) but not with changes in potassium conductance (405 ± 20 to 455 ± 30 μS/cm2, P < 0.16). Furthermore, acidification reduced the rheobase current by 26% at 4 mM K+ and increased the number of excitable fibers at elevated [K+]o. At 11 mM K+ and normal pH, a recovery of excitability and force similar to the observations with muscle acidification could be induced by reducing extracellular Cl− or by blocking the major muscle Cl− channel, ClC-1, with 30 μM 9-AC. It is concluded that recovery of excitability in K+-depressed muscles induced by muscle acidification is related to reduction in the inhibitory Cl− currents, possibly through inhibition of ClC-1 channels, and acidosis thereby reduces the Na+ current needed to generate and propagate an AP. Thus short term regulation of Cl− channels is important for maintenance of excitability in working muscle.

The performance of skeletal muscles depends on their ability to initiate and propagate action potentials along their outer membranes in response to motor signals from the central nervous system. This excitability of muscle fibres is related to the function of Na+ and K+ and Cl- channels and to steep chemical gradients for the ions across the cell membranes, i.e., the sarcolemma and T-tubular membranes. At rest, the chemical gradients for Na+ and K+ are maintained within close limits by the action of the Na+-K+ pump. During contractile activity, however, the muscles lose K+, which causes an increase in the concentration of K+ in the extracellular compartments of the body, the magnitude of which depends on the intensity of the exercise and the size of the muscle groups involved. Since the ensuing reduction in the chemical K+ gradient can have adverse effects on muscle excitability, it has repeatedly been suggested that, during intense exercise, the loss of K+ from muscle fibres can contribute to the complex set of mechanisms that leads to the development of muscle fatigue. In this review, aspects of the regulation of Na+-K+ homeostasis and excitability in contracting muscles is discussed within this context, together with the implications for the contractile function of skeletal muscles.

Aging and type 2 diabetes mellitus (T2DM) are associated with impaired skeletal muscle function and degeneration of the skeletal muscle microenvironment. However, the origin and mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscles of T2DM patients exibit pathologcial degenerative remodeling of the extracellular matrix that was associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90) - the FAPCD90+. We identified Platelet-derived growth factor (PDGF) signaling as key regulator of human FAP biology, as it promotes proliferation and collagen production at the expense of adipogenesis, an effect accompanied with a metabolic shift towards glycolytic lactate fermentation. FAPsCD90+ showed a PDGF-mimetic phenotype, with high proliferative activity and clonigenicity, increased production of extracellular matrix production and enhanced glycolysis. Importantly, the pathogenic phenotype of T2DM FAPCD90+ was reduced by treatment with the anti-diabet drug Metformin. These data identiy PDGF-driven conversion of a sub-population of FAPs as a key event in the pathogenic accumulation of extracellular matrix in T2DM muscles.