Some brief excerpts from Sports Med 2008; 38 (7): 527-540 Resistance Exercise Biology Manipulation of Resistance Exercise Programme variables Determines the Responses of Cellular and Molecular Signalling Pathways Barry A. Spiering Abstract Recent advances in molecular biology have elucidated some of the mechanisms that regulate skeletal muscle growth. Logically, muscle physiologists have applied these innovations to the study of resistance exercise (RE), as RE represents the most potent natural stimulus for growth in adult skeletal muscle. However, as this molecular-based line of research progresses to investigations in humans, scientists must appreciate the fundamental principles of RE to effectively design such experiments. Therefore, we present herein an updated paradigm of RE biology that integrates fundamental RE principles with the current knowledge of muscle cellular and molecular signalling. RE invokes a sequential cascade consisting of: (i) muscle activation; (ii) signalling events arising from mechanical deformation of muscle fibres, hormones, and immune/inflammatory responses; (iii) protein synthesis due to increased transcription and translation; and (iv) muscle fibre hypertrophy. In this paradigm, RE is considered an ‘upstream’ signal that determines specific downstream events. Therefore, manipulation of the acute RE programme variables (i.e. exercise choice, load, volume, rest period lengths, and exercise order) alters the unique ‘fingerprint’ of the RE stimulus and subsequently modifies the downstream cellular and molecular responses. Summary 1.1 Muscle activation In summary, exercise load, rate of force development, and muscle fatigue affect motor unit recruitment during RE. Motor unit recruitment (and the phenotype of the recruited motor units) must be carefully considered for responses and adaptations to RE because: (i) only those motor units recruited will respond and adapt to RE; (ii) heavy loads, explosive exercises, and/or significant muscle fatigue is necessary to activate type II motor units; (iii) type I and type II muscle fibres display differential signalling responses to muscle contraction; (iv) type II muscle fibres have a greater capacity for hypertrophy following RE training than type I fibres; and (v) different muscle groups possess varied percentages of type I and type II muscle fibres (for example, in humans the gastrocnemius is ~60% type I muscle fibres and the soleus is ~85% type I muscle fibres). Summary 1.2 Signalling events As previously mentioned in sections 1.2.2 and 1.2.3, RE-induced hormonal and immune responses increase satellite cell activity (i.e. activation, proliferation and differentiation). Hormones and cytokines activate these normally quiescent satellite cells and subsequently cause them to proliferate, differentiate and fuse to existing muscle fibres. Satellite cells thus contribute new nuclei to the existing pool within the muscle fibre. This is critical, because increasing the number of myonuclei en- hances the fibre’s capacity for transcription, protein synthesis and growth. The importance of satellite cells for muscle hypertrophy has been clearly dem- onstrated, as irradiation (a potent inhibitor of satel- cell activity) negates the increase in myonuclei, DNA content and muscle size that normally occurs following muscular overload. SUmmary 1.3 Protein SYnthesis Together, these results indicate that translational efficiency (i.e. mRNA translated per ribosome) is important for acute increases in protein synthesis during the initial hours/days of overload; however, increased transcriptional capacity (i.e. quantity of nuclei) via satellite cell fusion, and perhaps increased translational capacity (i.e. quantity of ribosomes), critically regulate long-term gains in muscle size. Summary 2.1 Exercise Choice Altogether, these studies indicate that, when muscle tension is equated, different muscle actions produce similar responses and adaptations. However, eccentric actions seem to be a more potent stimulus for muscle signalling because greater muscle tension can be developed. Although these findings indicate that eccentric muscle actions must be included to optimize adaptations to RE, disproportionate volumes of supplementary eccentric muscle actions might be counter-productive, as excessive muscle damage might ensue. Exercise load might impact the detection of sig- nalling responses following RE. Humans possess muscle groups of mixed fibre type, yet analysis of muscle signalling proteins typically requires homogenization of the muscle sample. Human muscle homogenate contains an array of type I, type IIa, and type IIx muscle fibres, eliminating the ability to analyse fibre type-specific results. This is relevant because the load employed during RE strongly affects motor unit (and hence, muscle fibre) recruitment. For example, low-load RE protocols might not recruit type II motor units (as suggested by the size principle), unless the exercise is performed explosively and/or there is significant muscle fatigue. Therefore, low-load RE protocols might result in significantly different signalling responses compared with heavy-load RE protocols. This is an important consideration, given that muscle contrac- tion-induced increases in p70 S6K phosphorylation occur mainly in type II muscle fibres. Summary 2.4 Rest Periods In summary, the direct influence of rest periods on mediating RE- induced muscle signalling responses is largely unexplored. Therefore, it is recommended that short rest periods can be used to stimulate hypertrophy and that long rest periods are used to maximize strength gains. Summary 2.5 Exercise Order The degree to which exercise order alters signalling responses to RE likely depends on the magnitude of change required of the other exercise variables (e.g. reduced 3. load and/or volume, increased rest) to compensate for altered neuromuscular performance. 3. Conclusion RE-induced muscle growth is an intricate, multifaceted process. Recruitment of motor units to produce force causes mechanical deformation of muscle fibres and stimulates hormonal and immune/inflammatory responses. These ‘upstream’ factors independently (and in some cases, inter-dependently) influence various muscle cell signalling pathways. In particular, the immediate response of the mTOR pathway and the prolonged influence of satellite cell activity are critical for mediating muscle growth. Manipulation of the acute RE programme variables (i.e. exercise choice, load, volume, rest periods and exercise order) dramatically impacts the signalling responses and subsequent adaptations to RE.