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POINT-COUNTERPOINT
Department of Physiology
University of Kentucky
Lexington, Kentucky
e-mail: karyn.esser{at}uky.edu
The stated point for this debate is that satellite cell addition is obligatory for skeletal muscle hypertrophy. The definition of the word "obligatory" is important for our argument and we interpret it to mean mandatory, necessary, or essential. Thus, as the counterpoint to this position, we will provide evidence of skeletal muscle hypertrophy in the absence of satellite cell addition.
Our position that skeletal muscle is capable of hypertrophy without the addition of satellite cells is supported by a large number of studies investigating the effect of 
-adrenergic agonists, such as clenbuterol and cimaterol, on skeletal muscle mass (1, 3, 6–9, 12, 14, 15, 17, 19, 20, 22–25, 29). These studies have been performed in a number of species, including mice, chicken, and sheep and have convincingly shown administration of -adrenergic agonists can induce skeletal muscle hypertrophy in the absence of any increase in DNA content or increases in myonuclear number (1, 6, 8, 9, 15, 19, 20, 23, 25). Thus one can look at muscle mass/DNA, protein content/DNA, or fiber diameter/DNA and the result for all of these variables is that there is a significant increase in the ratio following -adrenergic agonist treatment.
Early studies by Maltin and Delday (13) treated rats with clenbuterol and analyzed protein content, total DNA content, and the number of myonuclei per fiber in the soleus muscle. They reported a 15% increase in protein content with no change in total DNA or myonuclear number/fiber. Rehfeldt et al. (23) found that clenbuterol treatment in rats resulted in a 24–28% decrease in the ratio of nuclei to cytoplasmic in the EDL muscle. More recently, Sharma et al. (25), reported that mice administered clenbuterol showed a 26% increase in muscle mass with no change in total DNA content. They also documented that clenbuterol treatment induced hypertrophy with increases in muscle fiber cross sectional area in both red (i.e., type I or IIA) and white (i.e., type IIX or IIB) fibers. Many of these studies showed that while total DNA content does not increase with -adrenergic agonist treatment, there is a robust increase in total RNA and this likely reflects an increase in ribosomal RNA and protein synthetic capacity (5, 18). In fact, several studies have shown that rates of protein synthesis are increased in skeletal muscle, whereas rates of degradation are decreased in response to -adrenergic agonist treatment (2, 7, 10, 12, 14, 19, 26). Collectively, these studies provide strong evidence that -adrenergic agonists promote skeletal muscle hypertrophy by enhancing protein synthesis with no requirement for the addition of satellite cells.
In addition to the pharmacological studies, contractile activity has also been shown to induce hypertrophy of skeletal muscle in the absence of increases in DNA content. In a series of studies by Wong and Booth (27, 28), skeletal muscle hypertrophy in response to a controlled training paradigm was tested in both the tibialis anterior (TA) and gastrocnemius (GTN) muscles of rats. The eccentrically loaded TA muscle exhibited a 30% increase in muscle mass and 28% increase in protein content with no change in total DNA per muscle. Curiously enough, the concentrically loaded GTN muscle did exhibit an increase in total DNA content with no significant change in mass or total protein after 10 wk of training. Increases in total DNA and nuclear content without muscle growth have been documented previously in studies of skeletal muscle in response to low-frequency chronic stimulation (16, 21). Thus these results from the trained GTN muscle add to the literature demonstrating that increases in DNA/nuclear content are not sufficient to induce skeletal muscle growth.
The other set of studies that argue for skeletal muscle growth in the absence of satellite cell addition are studies in which DNA replication was inhibited either pharmacologically or by 
-irradiation. In these studies, the inhibition of DNA replication was not sufficient to prevent skeletal muscle growth. Fleckman et al. (4) treated male Sprague-Dawley rats with hydroxyurea and/or cytosine arabinoside to inhibit DNA synthesis following synergist ablation and found no difference in the magnitude of growth in the treated and untreated rats. They also demonstrated that the increase in muscle weight was the result of an increase in myofibrillar protein content. More recently, Lowe and Alway (11) exposed Japanese quails to -irradiation prior to applying stretch overload to the anterior latissimus dorsi (ALD) muscle. As reported in the paper, the ALD muscle in both the control and irradiated quails exhibited the same magnitude of growth with 100% increases in mass and protein content. In addition, the authors report that there was no increase in total DNA and no increase in BrdU incorporation in the hypertrophied ALD of the -irradiated quail. Zeman et al. (29) also found that -irradiation of the mdx mouse did not block growth of the EDL or GTN muscles in response to clenbuterol treatment. Thus we feel that these studies provide an additional line of support for our position that skeletal muscle can hypertrophy in the absence of satellite cell proliferation and/or addition.
In summary, we provided evidence from studies of pharmacological and contraction-induced skeletal muscle growth in which satellite cell addition does not occur as measured by DNA content or nuclear number. We also present studies in which inhibition of satellite cell proliferation does not inhibit skeletal muscle growth. We believe that the evidence we provide clearly makes our argument that satellite cell addition is not obligatory for skeletal muscle growth.
REFERENCES
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  J. M. Gonzalez, R. D. Dijkhuis, D. D. Johnson, J. N. Carter, and S. E. Johnson Differential response of cull cow muscles to the hypertrophic actions of ractopamine-hydrogen chloride J Anim Sci, December 1, 2008; 86(12): 3568 - 3574. [Abstract] [Full Text] [PDF]
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 M. Sandri Signaling in Muscle Atrophy and Hypertrophy Physiology, June 1, 2008; 23(3): 160 - 170. [Abstract] [Full Text] [PDF]
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