Capturing the imagination since its inception as a collaborative factor in muscle growth, creatine remains the quintessential hot topic in muscle physiology. If there were a continuum of sentiment on the ergogenic potential of supplements, creatine would lie favorably at the leading edge. A large body of work confirms that creatine is indispensable for muscular performance during repeated sets of intense exercise. Of interest, recent studies have provided insight into the versatility of creatine; shifting the paradigm towards satellite cell dynamics.
Creatine: Mechanism of Action
Skeletal muscle fibers are enriched with proteins (actin and myosin), that require energy to generate force during muscle contraction. The universal energy currency for all cells, ATP, is generated by oxidative phosphorylation in subcellular compartments known as mitochondria. Given that these contractile proteins are distributed throughout the myofiber, and ATP diffuses poorly from its origin in the mitochondria; the energy potential of ATP is transferred to an alternate molecule: creatine. In contrast to ATP, phosphocreatine (PCr) readily diffuses throughout the cell due to favorable physiochemical properties.
A number of studies support the biologic tenet that phosphocreatine replenishes ATP levels during repeated sets of intense physical activity. As muscular contraction is dependent on ATP, these findings suggest that increasing the availability of PCr may result in higher levels of force production during repeated sets of resistance training. In addition, raising intramuscular creatine levels would enhance the kinetics of ATP replenishment during recovery between sets. Importantly, achieving those final repetitions on the third and fourth set of a resistance exercise is associated with enhanced muscular adaptation, and moreover, concordant with the fundamental philosophy of progressive resistance training. In the course of accelerating upwards during the concentric phase of a squat/deadlift, or writhing beneath the bench press, increased capacity (creatine-mediated) for those last vital repetitions translates into enhanced muscle growth.
Creatine: the quintessential to the sublime
Although PCr is commonly associated with the bioenergetics of muscle contraction, increasing evidence confirms that the functional role of PCr extends to several physiologic niches. Of note, PCr enhances ATP repletion in multiple cells with high-energy demands including neurons, skeletal muscle, and spermatozoa. Toward this end, PCr is a highly-conserved, temporally-regulated, energy buffer important for a multiplicity of reasons in several biologic systems. Adding to this growing body of knowledge, we describe recent findings illuminating novel roles for PCr in satellite cell-dependent processes indispensable for muscle growth.
Resistance training is associated with muscle damage and soreness. At the molecular level this process is characterized by a disruption in the cell membrane (sarcolemma) surrounding each muscle fiber, and an infiltration of inflammatory cells. Intuitively, compromising the integrity of the sarcolemma prompts a release of intracellular constituents (including PCr) to the extracellular niche. Of interest, a localized pool of stem cells, called satellite cells, surround each myofiber. In response to signals released from injured muscle, satellite cells undergo an ordered process of events indispensable for muscle repair.
Expansion of satellite cells and their progeny provide a pool of cells expressing muscle-specific proteins. These cells fuse with injured fibers to restore muscle architecture and function. This leads us to a compelling question: could muscle remodeling after damage be an energy-dependent process, and moreover, are satellite cell dynamics (migration, expansion, differentiation, and/or fusion) enhanced in a creatine-dependent manner?
While studying the molecular basis of muscle growth I described a model (O'Connor et al., Journal of Physiology), in which creatine sustains localized ATP-dependent reactions at the interface of fusing muscle cells. Of interest, muscle cell fusion restores muscle architecture during repair after injury; activated satellite cells fuse together to form new myofibers, or fuse with damaged myofibers during regeneration.
To capture the imagination, satellite cells migrate to sites of damage in response to chemotactic signals emanating from muscle fibers. Therein, satellite cells align themselves in preparation for fusion. Satellite cells activate proteins on their surface providing a scaffold for adhesion with injured myofibers. Following adhesion, the membranes of satellite cells and muscle fibers actually merge. Fusion of intracellular constituents' completes the regenerative process. Importantly, a set of cytoskeletal proteins assemble at the interface of opposing cells to regulate this fusion phase. Such extensive cellular reorganization preceding satellite cell fusion is highly energy dependent. Of note, intracellular energy demands are met via an ordered continuum of oxidative phosphorylation, anaerobic glycolysis and finally, PCr hydrolysis. In contrast to other energy sources, PCr hydrolysis provides maximal rates of ATP production with minimal energy cost and no adverse effect on intracellular pH. While glucose oxidation may provide sufficient energy for satellite cell fusion, glycolysis is associated with intracellular acidification through proton accumulation. This may have adverse effects on proteins actively engaging in the fusion process. On this basis, why wouldn't satellite cells rely on PCr for the energy demands of muscle remodeling?
Evidence for creatine-mediated benefits in satellite cell fusion is provided in the accompanying figure. Mindful to add, these are results from in vitro cell culture studies. Therein, the addition of creatine to differentiating satellite cells increased the number of nuclei contained in myotubes (the differentiated progeny of satellite cells; analogous to myofibers in vivo). The myonuclear domain hypothesis of muscle growth, elegantly described by Dr Scott Connelly on the HEAVY MUSCLE RADIO (click here to listen) podcast, establishes that coordinated increases in nuclei and cytoplasmic volume occur during muscle growth. Nuclei are intracellular programming centers. They contain a genetic blueprint/template for the synthesis of new proteins within their immediate vicinity. As each nucleus regulates a finite volume of cytoplasm, there must be coordinated increments in nuclei with increased muscle size. Thus, adding nuclei to growing/regenerating myofibers through satellite cell-dependent processes is indispensable for muscle growth. We anticipate that future studies, using various models of regeneration after muscle damage, will extend these findings on phosphocreatine and satellite cell-dependent muscle growth.
Additional Reading:
Subscribe to RxMuscle on Youtube
